氟非尼酮治疗糖尿病肾病db/db小鼠肾纤维化及其作用机制的研究
|
摘要
研究背景
糖尿病肾病(DN)是糖尿病的常见严重并发症之一,常发展成为终末期肾病(ESRD)。目前,临床治疗手段主要是控制血糖和抗高血压,但疗效有限,只能减慢糖尿病肾病向肾功能衰竭的进程。因此,必须针对糖尿病肾病的主要病理机制研发新的治疗药物。糖尿病肾病组织学损伤的主要特征是胶原、纤维连接蛋白等细胞外基质(ECM)成分在肾小球系膜和肾小管间质进行性沉积,最终导致不可逆的肾纤维化。近年来,不少研究着力于寻找能有效抑制ECM在组织中沉积而治疗糖尿病肾病的药物,取得了一些前景诱人的成果。AKF-PD是
一种新合成的低分子量化合物。我们研究组最近报道,在体外培养的小鼠肾小球系膜细胞和大鼠肾小管上皮细胞中,AKF-PD能够抑制转化生长因子-β1(transforming growth factor-β1, TGF-β1)刺激后引起的ECM的产生。
目的
以糖尿病肾病db/db小鼠和MES13肾小球系膜细胞为实验对象,观察AKF-PD对肾纤维化的治疗效果,并深入揭示其作用机制,为研发治疗糖尿病肾病的抗纤维化新药提供实验证据。
方法
1.10周龄雄性db/db小鼠分为1个不给药模型组和3个AKF-PD给药组(剂量分别为每日125、500、1000mg/kg体重)；相同周龄雄性db/m小鼠作为正常对照组。称体重和测血糖后,AKF-PD溶于羧甲基纤维素钠溶液作灌胃给药,不给药db/db组和db/m组小鼠作等量羧甲基纤维素钠溶液灌胃,各组小鼠每天灌胃一次,持续12周。实验期间2周一次测血糖水平。实验12周后,小鼠分单只置于代谢笼,收集24h尿标本。用ELISA法测定尿白蛋白浓度。处死各组小鼠。称体重后,取双侧肾脏,称肾重和剪取肾皮质。制备肾皮质组织切片,作PAS染色。光镜下观察组织切片,按每只小鼠20个肾小球,分5级(0-4级)进行每个肾小球损伤程度的评分,并计算肾小球系膜基质扩展指数(GMI)。用ELISA法测定肾皮质组织匀浆TGF-β1蛋白水平。以β-actin为内参作标化,real-time PCR方法检测肾皮质组织Ⅰ型胶原、Ⅳ型胶原、纤维连接蛋白(FN)、金属蛋白酶组织抑制因子-1(TIMP-1)、α-平滑肌肌动蛋白(a-SMA)mRNA的相对丰度。用肾皮质组织裂解产物作SDS-PAGE,进行western blot检测。以a-tublin为内参标化,检测TIMP-1、α-SMA蛋白质的相对含量。
2.细胞周期同步化处理的小鼠肾小球系膜细胞系(MES-13)细胞分为6个组：(1)NG组(正常浓度葡萄糖,,-5.6mmol/L);(2)HG组(高浓度葡萄糖,25mmol/L);(3) AKF-PD组(HG+400μg/mLAKF-PD);(4)PFD组(HG+400μg/mL吡非尼酮)；(5)Los组(HG+21μmol/L氯沙坦)；(6)OC组(渗透压对照组,NG+19.4mmol/L甘露醇)。各组细胞培养72h后,收集细胞和上清。用ELISA法测定细胞培养上清液的TGF-β1蛋白水平。以β-actin为内参,real-timePCR方法检测细胞Ⅰ型胶原、Ⅳ型胶原、TIMP-1、α-SMA mRNA的相对丰度。用细胞裂解产物作SDS-PAGE,进行western blot检测。以a-tublin为内参,检测TIMP-1、α-SMA蛋白质的相对含量。
结果
dbldb组小鼠的肾重明显大于db/m组小鼠(P<0.05)。与不给药组相比,AKF-PD给药组dbldb小鼠的肾重明显减轻(P<0.05),以500mg/kg剂量组效果最明显(P<0.01)。
dbldb小鼠有严重的白蛋白尿,24h尿白蛋白排泄量达240.26±76.24μg,比db/m小鼠组升高8倍(P<0.01)。AKF-PD给药显著减轻dbldb小鼠的白蛋白尿(P<0.01),最大有效剂量为500mg/kg,可使24h尿白蛋白排泄量下降58.5%。
从实验开始至实验结束,dbldb小鼠始终有严重的高血糖,血糖一般维持于30mmol/L以上。AKF-PD给药组与不给药组dbldb小鼠的血糖水平差异无显著性意义。
与db/m小鼠相比,dbldb小鼠的肾小球系膜基质PAS阳性染色区明显扩大,肾小球系膜基质扩展指数(GMI)显著增加(P<0.01)。与不给药组dbldb小鼠比,AKF-PD给药组dbldb小鼠的肾小球系膜基质PAS阳性染色区明显缩小,GMI显著减低(P<0.05),其中,500mg/kg体重剂量组的GMI值减低约55.8%(P<0.01)。
dbldb小鼠肾皮质的Ⅰ型胶原、Ⅳ型胶原和纤维连接蛋白的mRNA表达水平比db/m小鼠显著升高(P<0.01)。AKF-PD显著抑制三种细胞外基质成分mRNA的表达(P<0.05)
dbldb小鼠肾皮质的TGF-β1mRNA和蛋白表达水平比db/m小鼠显著升高(P<0.01)。AKF-PD显著抑制dbldb小鼠肾皮质TGF-β1的表达(P<0.05)。
dbldb小鼠肾皮质TIMP-1mRNA和蛋白表达水平显著高于db/m小鼠(P<0.01)。AKF-PD给药对dbldb小鼠肾皮质TIMP-1的高表达具有显著下调作用(P<0.01)。
dbldb小鼠肾皮质α-SMA mRNA和蛋白的表达水平显著高于db/m小鼠(P<0.01)。AKF-PD给药明显抑制dbldb小鼠肾皮质α-SMA的表达(P<0.05),其最大有效剂量为500mg/kg。
与NG组相比,HG组MES-13细胞的Ⅰ型胶原、Ⅳ型胶原mRNA表达水平显著增高(P<0.01)。与HG组相比,AKF-PD组、PFD组与氯沙坦组MES-13细胞的Ⅰ型胶原、Ⅳ型胶原mRNA表达水平明显降低(P<0.05)。且三种药物的作用相似。
与NG组相比,HG组MES-13细胞的TGF-β1mRNA和蛋白表达水平显著上调(P<0.01)；与HG组相比,AKF-PD组、PFD组与氯沙坦组MES-13细胞的TGF-β1mRNA和蛋白表达水平明显降低(P<0.05)。而AKF-PD与PFD能使TGF-β1蛋白表达下调到接近NG组的水平,氯沙坦的这种作用较弱。
与NG组相比,HG组MES-13细胞的TIMP-1mRNA和蛋白表达水平显著上调(P<0.01)；与HG组相比,AKF-PD组、PFD组与氯沙坦组MES-13细胞的TIMP-1mRNA和蛋白表达水平明显降低(P<0.01)。且三种药物的作用相似。
与NG组相比,HG组MES-13细胞的α-SMA蛋白表达水平显著增高(P<0.01)；与HG组相比,AKF-PD组、PFD组与氯沙坦组MES-13细胞的α-SMA蛋白表达水平明显降低(P<0.05)。且三种药物的作用相似。
结论：
AKF-PD长期给药对db/db小鼠的糖尿病肾病有治疗作用,可显著减少糖尿病肾病db/db小鼠24小时尿白蛋白排泄量,减轻肾小球系膜基质扩展,抑制肾组织Ⅰ型胶原、Ⅳ型胶原、纤维连接蛋白等细胞外基质成分及TGF-β1、α-SMA、TIMP-1的表达。AKF-PD对db/db小鼠的高血糖无明显影响。
AKF-PD能明显抑制高糖刺激下小鼠肾小球系膜细胞(MES-13)的Ⅰ型胶原、Ⅳ型胶原、TGF-β1、α-SMA、TIMP-1表达。
AKF-PD治疗糖尿病肾病肾纤维化的作用机制与其抑制肾小球系膜细胞TGF-β1的产生,抑制肾小球系膜细胞向肌成纤维细胞表型的转分化,抑制细胞外基质降解调节分子TIMP-1表达,调节肾脏细胞外基质降解平衡有关。
Background
Diabetic nephropathy (DN) is the common and serious complication of diabetes that often progresses to end-stage renal disease (ESRD). Available therapies only slow but do not halt the progression of renal dysfunction in diabetic nephropathy in clinical settings. It is therefore necessary to develop new therapeutic agents that target major pathological mechanisms of diabetic nephropathy. The histological injury of diabetic nephropathy is mainly characterized by the progressive accumulation of extracellular matrix (ECM) components such as collagen and fibronectin in the glomerular mesangium and tubulointerstitium, which ultimately results in the irreversible fibrosis of kidneys. Considerable efforts are being made to explore therapeutic agents effectively inhibiting ECM accumulation to treat diabetic nephropathy, and promising results have been obtained in recent years. Fluorofenidone (1-(3-fluorophenyl)-5-methyl-2-(1H)-pyridone, AKF-PD) is a novel low-molecular-weight pyridone agent. We recently reported that AKF-PD exerts a strong antifibrotic effect and inhibits TGF-β-stimulated production of ECM in mouse mesangial cells and rat proximal tubular epithelial cells in culture.
Objective
The present study was designed to evaluate the potential therapeutic efficacy of AKF-PD on kidney fibrosis and to obtain an insight into its underlying mechanisms of action in db/db mice with diabetic nephropathy and cultured murine mesangial-derived MES13cells exposed to high glucose, in order that this pyridone agent can be developed into a potent antifibrotic drug for the therapy of diabetic kidney disease.
Method
1. Male db/db mice and age-matched dblm mice were used for this study. Mice at10weeks of age were divided into five groups:a dblm mice group, a dbldb mice group, and three AKF-PD treatment groups in which dbldb mice were administered with AKF-PD (dissolved in CMCNa solution) at doses of125mg,500mg or1000mg·kg body weight-1·day-1respectively. The mice of dblm and dbldb groups were administered with CMCNa solution alone. The administration of AKF-PD or CMCNa solution was performed by gavage daily for a period of12weeks.
Mice were individually housed in metabolic cages and the urine samples were collected over24hours. Levels of urinary albumin were quantified using a mouse albumin ELISA Kit.
Mice were anesthetized with ether, and then blood samples were obtained from the tail vein. Levels of blood glucose were determined with an Automatic Analyzer.
The ether-anesthetized mice were sacrificed at the end of12-wk treatment. The kidneys were rapidly dissected out, weighed and separate the cortices. Sections of renal tissues were prepared and stained with periodic acid-Schiff (PAS).20glomeruli were evaluated for each mouse. The degree of damage in each glomerulus was assessed using a semi-quantitative (grade0-4) scoring method. The glomerular matrix expansion index (GMI) was calculated according to the number of glomeruli in each grade of mesangial expansion.
TGF-β1protein levels in homogenates of renal cortices were determined by using a TGF-β1ELISA kit.
Total RNA was isolated from kidney tissues. The cDNA was synthesized from total RNA. RT-PCR primers for α1(I)collagen, α1(IV)collagen, fibronectin, TGF-(31, tissue inhibitors-1of metalloproteinases (TIMP-1), α-smooth muscle actin (a-SMA) and β-actin were ordered from Sangon Inc. Amplification reactions were performed in duplicate with SYBR Green PCR reagent kit. The relative abundance of mRNA was standardized with β-actin mRNA as the invariant control.
The lysates of kidney cortex tissues were subjected to SDS-PAGE and then electroblotted onto polyvinylidene difluoride (PVDF) membranes. Following the blocking step, the electroblotted membranes were immunoblotted with the primary antibodies against a-SMA, TIMP1, a-tublin respectively. The membranes immunoblotted were incubated with horseradish peroxidase-labelled secondary antibodies. After washing, the membranes were exposed to X-ray film. The bands of resulting autoradiographs were quantified densitometrically using Bandscan software.
2. The synchronized MES-13cells were assigned to six groups:(1) NG, medium containing normal glucose concentration (-5.6mmol/L);(2) HG, medium containing25mmol/L glucose;(3) AKF-PD, medium containing HG and400μg/mL AKF-PD;(4) PFD, medium containing HG and400μg/mL pirfenidone;(5) Los, medium containing HG and2μmol/L losartan;(6) OC, medium containing NG and19.4mmol/L mannitol as an osmotic control. The cells in all six groups were cultured for72h, and then cells and culture supernatants were collected for RT-PCR and Western blotting.
TGF-β1protein levels in supernatants from MES-13cell cultures were determined by using a TGF-β1ELISA kit.
Total RNA was isolated from MES-13cells. The cDNA was synthesized from total RNA. RT-PCR primers for α1(Ⅰ)collagen, al(IV)collagen, fibronectin, TGF-β1, tissue inhibitors-1of metalloproteinases (TIMP-1), cc-smooth muscle actin (a-SMA) and β-actin were ordered from Sangon Inc. Amplification reactions were performed in duplicate with SYBR Green PCR reagent kit. The relative abundance of mRNA was standardized with β-actin mRNA as the invariant control.
The lysates of MES-13cells were subjected to SDS-PAGE and then electroblotted onto polyvinylidene difluoride (PVDF) membranes. Following the blocking step, the electroblotted membranes were immunoblotted with the primary antibodies against a-SMA, TIMP1, a-tublin respectively. The membranes immunoblotted were incubated with horseradish peroxidase-labelled secondary antibodies. After washing, the membranes were exposed to X-ray film. The bands of resulting autoradiographs were quantified densitometrically using Bandscan software.
Results
Kidney weights of diabetic db/db mice were markedly greater than those of dblm mice(P<0.05). Treatment with AKF-PD reduced the kidney hypertrophy of diabetic dbldb mice, as indicated by decreased kidney weight and kidney/body weight ratio in treated dbldb mice compared with untreated dbldb mice. The diminished effect of AKF-PD on the renal hypertrophy was most obvious at a dosage of500mg/kg body weight per day(P<0.01).
Diabetic db/db mice had heavy albuminuria. The urinary albumin excretion rate was higher by8-fold in dbldb mice than that in dblm mice group(P<0.01). The administration of AKF-PD significantly attenuated albuminuria of diabetic db/db mice and a dose of500mg/kg body weight was the peak-effective dose at which24-h urinary albumin excretion declined by58.5percent(P<0.01).
The dbldb mice remained hyperglycemic throughout the experimental period, and their mean blood glucose levels were about5times as high as in dblm mice(P<0.01). No significant differences of blood glucose were observed between AKF-PD treated and untreated dbldb mice groups.
In comparison with dblm mice, PAS-positive mesangial matrix areas were substantially enlarged and the glomerular mesangial expansion index (GMI) i.e., the ratio of mesangial matrix area divided by the tuft area, was significantly increased in dbldb mice(P<0.01). Compared with untreated dbldb mice group, the PAS-positive mesangial matrix areas and GMIs decreased obviously in AKF-PD-treated dbldb mice groups(P<0.05) and GMI was reduced by approximately55.8%at the dose of500mg/kg body weight(P<0.01).
The mRNA levels of α1(Ⅰ)collagen, α1(Ⅳ)collagen and fibronectin in renal cortex of db/db mice were3-4times higher than those in dblm mice(P<0.01). The up-regulated expressions of the three ECM components at the transcriptional level were dose-dependently reduced in renal cortex of diabetic dbldb mice subjected to AKF-PD treatment(P<0.05).
Diabetic db/db mice had the marked upregulation of expression TGF-β1mRNA and protein in renal cortex compared with dblm mice(P<0.01). AKF-PD treatment reduced significantly the enhanced expression of TGF-(31mRNA and protein in dbldb mice(P<0.05).
Compared with dblm mice, expression of renal cortex TIMP-1was markedly upregulated in diabetic dbldb mice as indicated by real-time RT-PCR and western blotting(P<0.01). The upregulated renal expressions of TIMP-1mRNA and protein in dbldb mice were significantly inhibited by AKF-PD treatment(P<0.01).
The mRNA and protein expressions of a-SMA in renal cortex of diabetic dbldb mice were markedly upregulated compared with dblm mice(P<0.01). AKF-PD administration to dbldb mice inhibited dramatically the upregulated expressions of a-SMA mRNA and protein in renal cortex(P<0.05), and the maximally effective doses were about500mg/kg body weight per day.
The expression of α1(Ⅰ) and α1(Ⅳ) collagen mRNAs in HG group of MES-13cells was obviously increased compared with NG group(P<0.01). The addition of AKF-PD, PFD or losartan to culture media inhibited significantly the high glucose-induced upregulation of α1(Ⅰ) and α1(Ⅳ) collagen mRNA expression in mesangial cells(P<0.05), and there was no significant difference among the three agents.
Each of AKF-PD, PFD and losartan can inhibit significantly the up-regulated expression of TGF-β1mRNA induced by high glucose in MES-13cells in vitro(P<0.01), and differences between the three agents were not statistically significant. AKF-PD, PFD and losartan also inhibit significantly the high glucose-stimulated upregulation of TGF-β1protein expression in the cultured mesangial cells(P<0.05). However, both AKF-PD and PFD can reverse the expression of TGF-β1protein approximately to the level of NG group, but this inhibitory effect of losartan seemed to be slightly weaker.
Both mRNA and protein expression of TIMP-1by cultured mesangial cells were remarkably increased in HG group compared with the NG group (P<0.01). The levels of TIMP-1mRNA and protein in the AKF-PD-, PFD-and losartan-treatment groups were obviously lower than those in HG group(P<0.01). No significant difference in TIMP-1was observed among these three treatment groups.
In comparison with NG group, the expression level of a-SMA protein in HG group was significantly higher(P<0.01). The addition of AKF-PD, PFD or losartan to the culture media significantly inhibited the expression of a-SMA protein by cultured mesangial cells under high glucose conditions(P<0.05). The differences in a-SMA protein expression among these three agents were not significant.
Conclusion
This study demonstrates that long-term administration of AKF-PD attenuates renal hypertrophy, mesangial matrix expansion and albuminuria in the diabetic db/db mice despite continued hyperglycemia. Upregulated expressions of several ECM components, TIMP-1, TGF-β1and a-SMA at the transcriptional and protein levels are significantly inhibited by AKF-PD treatment in renal cortex of db/db mice and cultured mesangial cells under high glucose conditions. The results presented here suggest that AKF-PD is able to ameliorate the ECM production and degradation imbalance via the inhibition of TGF-β1pathway, resulting in attenuation of renal fibrosis associated with diabetic state. Therefore, use of AKF-PD as a potent antifibrotic agent holds great promise for the therapy of diabetic nephropathy.
糖尿病肾病(DN)是糖尿病的常见严重并发症之一,常发展成为终末期肾病(ESRD)。目前,临床治疗手段主要是控制血糖和抗高血压,但疗效有限,只能减慢糖尿病肾病向肾功能衰竭的进程。因此,必须针对糖尿病肾病的主要病理机制研发新的治疗药物。糖尿病肾病组织学损伤的主要特征是胶原、纤维连接蛋白等细胞外基质(ECM)成分在肾小球系膜和肾小管间质进行性沉积,最终导致不可逆的肾纤维化。近年来,不少研究着力于寻找能有效抑制ECM在组织中沉积而治疗糖尿病肾病的药物,取得了一些前景诱人的成果。AKF-PD是
一种新合成的低分子量化合物。我们研究组最近报道,在体外培养的小鼠肾小球系膜细胞和大鼠肾小管上皮细胞中,AKF-PD能够抑制转化生长因子-β1(transforming growth factor-β1, TGF-β1)刺激后引起的ECM的产生。
目的
以糖尿病肾病db/db小鼠和MES13肾小球系膜细胞为实验对象,观察AKF-PD对肾纤维化的治疗效果,并深入揭示其作用机制,为研发治疗糖尿病肾病的抗纤维化新药提供实验证据。
方法
1.10周龄雄性db/db小鼠分为1个不给药模型组和3个AKF-PD给药组(剂量分别为每日125、500、1000mg/kg体重)；相同周龄雄性db/m小鼠作为正常对照组。称体重和测血糖后,AKF-PD溶于羧甲基纤维素钠溶液作灌胃给药,不给药db/db组和db/m组小鼠作等量羧甲基纤维素钠溶液灌胃,各组小鼠每天灌胃一次,持续12周。实验期间2周一次测血糖水平。实验12周后,小鼠分单只置于代谢笼,收集24h尿标本。用ELISA法测定尿白蛋白浓度。处死各组小鼠。称体重后,取双侧肾脏,称肾重和剪取肾皮质。制备肾皮质组织切片,作PAS染色。光镜下观察组织切片,按每只小鼠20个肾小球,分5级(0-4级)进行每个肾小球损伤程度的评分,并计算肾小球系膜基质扩展指数(GMI)。用ELISA法测定肾皮质组织匀浆TGF-β1蛋白水平。以β-actin为内参作标化,real-time PCR方法检测肾皮质组织Ⅰ型胶原、Ⅳ型胶原、纤维连接蛋白(FN)、金属蛋白酶组织抑制因子-1(TIMP-1)、α-平滑肌肌动蛋白(a-SMA)mRNA的相对丰度。用肾皮质组织裂解产物作SDS-PAGE,进行western blot检测。以a-tublin为内参标化,检测TIMP-1、α-SMA蛋白质的相对含量。
2.细胞周期同步化处理的小鼠肾小球系膜细胞系(MES-13)细胞分为6个组：(1)NG组(正常浓度葡萄糖,,-5.6mmol/L);(2)HG组(高浓度葡萄糖,25mmol/L);(3) AKF-PD组(HG+400μg/mLAKF-PD);(4)PFD组(HG+400μg/mL吡非尼酮)；(5)Los组(HG+21μmol/L氯沙坦)；(6)OC组(渗透压对照组,NG+19.4mmol/L甘露醇)。各组细胞培养72h后,收集细胞和上清。用ELISA法测定细胞培养上清液的TGF-β1蛋白水平。以β-actin为内参,real-timePCR方法检测细胞Ⅰ型胶原、Ⅳ型胶原、TIMP-1、α-SMA mRNA的相对丰度。用细胞裂解产物作SDS-PAGE,进行western blot检测。以a-tublin为内参,检测TIMP-1、α-SMA蛋白质的相对含量。
结果
dbldb组小鼠的肾重明显大于db/m组小鼠(P<0.05)。与不给药组相比,AKF-PD给药组dbldb小鼠的肾重明显减轻(P<0.05),以500mg/kg剂量组效果最明显(P<0.01)。
dbldb小鼠有严重的白蛋白尿,24h尿白蛋白排泄量达240.26±76.24μg,比db/m小鼠组升高8倍(P<0.01)。AKF-PD给药显著减轻dbldb小鼠的白蛋白尿(P<0.01),最大有效剂量为500mg/kg,可使24h尿白蛋白排泄量下降58.5%。
从实验开始至实验结束,dbldb小鼠始终有严重的高血糖,血糖一般维持于30mmol/L以上。AKF-PD给药组与不给药组dbldb小鼠的血糖水平差异无显著性意义。
与db/m小鼠相比,dbldb小鼠的肾小球系膜基质PAS阳性染色区明显扩大,肾小球系膜基质扩展指数(GMI)显著增加(P<0.01)。与不给药组dbldb小鼠比,AKF-PD给药组dbldb小鼠的肾小球系膜基质PAS阳性染色区明显缩小,GMI显著减低(P<0.05),其中,500mg/kg体重剂量组的GMI值减低约55.8%(P<0.01)。
dbldb小鼠肾皮质的Ⅰ型胶原、Ⅳ型胶原和纤维连接蛋白的mRNA表达水平比db/m小鼠显著升高(P<0.01)。AKF-PD显著抑制三种细胞外基质成分mRNA的表达(P<0.05)
dbldb小鼠肾皮质的TGF-β1mRNA和蛋白表达水平比db/m小鼠显著升高(P<0.01)。AKF-PD显著抑制dbldb小鼠肾皮质TGF-β1的表达(P<0.05)。
dbldb小鼠肾皮质TIMP-1mRNA和蛋白表达水平显著高于db/m小鼠(P<0.01)。AKF-PD给药对dbldb小鼠肾皮质TIMP-1的高表达具有显著下调作用(P<0.01)。
dbldb小鼠肾皮质α-SMA mRNA和蛋白的表达水平显著高于db/m小鼠(P<0.01)。AKF-PD给药明显抑制dbldb小鼠肾皮质α-SMA的表达(P<0.05),其最大有效剂量为500mg/kg。
与NG组相比,HG组MES-13细胞的Ⅰ型胶原、Ⅳ型胶原mRNA表达水平显著增高(P<0.01)。与HG组相比,AKF-PD组、PFD组与氯沙坦组MES-13细胞的Ⅰ型胶原、Ⅳ型胶原mRNA表达水平明显降低(P<0.05)。且三种药物的作用相似。
与NG组相比,HG组MES-13细胞的TGF-β1mRNA和蛋白表达水平显著上调(P<0.01)；与HG组相比,AKF-PD组、PFD组与氯沙坦组MES-13细胞的TGF-β1mRNA和蛋白表达水平明显降低(P<0.05)。而AKF-PD与PFD能使TGF-β1蛋白表达下调到接近NG组的水平,氯沙坦的这种作用较弱。
与NG组相比,HG组MES-13细胞的TIMP-1mRNA和蛋白表达水平显著上调(P<0.01)；与HG组相比,AKF-PD组、PFD组与氯沙坦组MES-13细胞的TIMP-1mRNA和蛋白表达水平明显降低(P<0.01)。且三种药物的作用相似。
与NG组相比,HG组MES-13细胞的α-SMA蛋白表达水平显著增高(P<0.01)；与HG组相比,AKF-PD组、PFD组与氯沙坦组MES-13细胞的α-SMA蛋白表达水平明显降低(P<0.05)。且三种药物的作用相似。
结论：
AKF-PD长期给药对db/db小鼠的糖尿病肾病有治疗作用,可显著减少糖尿病肾病db/db小鼠24小时尿白蛋白排泄量,减轻肾小球系膜基质扩展,抑制肾组织Ⅰ型胶原、Ⅳ型胶原、纤维连接蛋白等细胞外基质成分及TGF-β1、α-SMA、TIMP-1的表达。AKF-PD对db/db小鼠的高血糖无明显影响。
AKF-PD能明显抑制高糖刺激下小鼠肾小球系膜细胞(MES-13)的Ⅰ型胶原、Ⅳ型胶原、TGF-β1、α-SMA、TIMP-1表达。
AKF-PD治疗糖尿病肾病肾纤维化的作用机制与其抑制肾小球系膜细胞TGF-β1的产生,抑制肾小球系膜细胞向肌成纤维细胞表型的转分化,抑制细胞外基质降解调节分子TIMP-1表达,调节肾脏细胞外基质降解平衡有关。
Background
Diabetic nephropathy (DN) is the common and serious complication of diabetes that often progresses to end-stage renal disease (ESRD). Available therapies only slow but do not halt the progression of renal dysfunction in diabetic nephropathy in clinical settings. It is therefore necessary to develop new therapeutic agents that target major pathological mechanisms of diabetic nephropathy. The histological injury of diabetic nephropathy is mainly characterized by the progressive accumulation of extracellular matrix (ECM) components such as collagen and fibronectin in the glomerular mesangium and tubulointerstitium, which ultimately results in the irreversible fibrosis of kidneys. Considerable efforts are being made to explore therapeutic agents effectively inhibiting ECM accumulation to treat diabetic nephropathy, and promising results have been obtained in recent years. Fluorofenidone (1-(3-fluorophenyl)-5-methyl-2-(1H)-pyridone, AKF-PD) is a novel low-molecular-weight pyridone agent. We recently reported that AKF-PD exerts a strong antifibrotic effect and inhibits TGF-β-stimulated production of ECM in mouse mesangial cells and rat proximal tubular epithelial cells in culture.
Objective
The present study was designed to evaluate the potential therapeutic efficacy of AKF-PD on kidney fibrosis and to obtain an insight into its underlying mechanisms of action in db/db mice with diabetic nephropathy and cultured murine mesangial-derived MES13cells exposed to high glucose, in order that this pyridone agent can be developed into a potent antifibrotic drug for the therapy of diabetic kidney disease.
Method
1. Male db/db mice and age-matched dblm mice were used for this study. Mice at10weeks of age were divided into five groups:a dblm mice group, a dbldb mice group, and three AKF-PD treatment groups in which dbldb mice were administered with AKF-PD (dissolved in CMCNa solution) at doses of125mg,500mg or1000mg·kg body weight-1·day-1respectively. The mice of dblm and dbldb groups were administered with CMCNa solution alone. The administration of AKF-PD or CMCNa solution was performed by gavage daily for a period of12weeks.
Mice were individually housed in metabolic cages and the urine samples were collected over24hours. Levels of urinary albumin were quantified using a mouse albumin ELISA Kit.
Mice were anesthetized with ether, and then blood samples were obtained from the tail vein. Levels of blood glucose were determined with an Automatic Analyzer.
The ether-anesthetized mice were sacrificed at the end of12-wk treatment. The kidneys were rapidly dissected out, weighed and separate the cortices. Sections of renal tissues were prepared and stained with periodic acid-Schiff (PAS).20glomeruli were evaluated for each mouse. The degree of damage in each glomerulus was assessed using a semi-quantitative (grade0-4) scoring method. The glomerular matrix expansion index (GMI) was calculated according to the number of glomeruli in each grade of mesangial expansion.
TGF-β1protein levels in homogenates of renal cortices were determined by using a TGF-β1ELISA kit.
Total RNA was isolated from kidney tissues. The cDNA was synthesized from total RNA. RT-PCR primers for α1(I)collagen, α1(IV)collagen, fibronectin, TGF-(31, tissue inhibitors-1of metalloproteinases (TIMP-1), α-smooth muscle actin (a-SMA) and β-actin were ordered from Sangon Inc. Amplification reactions were performed in duplicate with SYBR Green PCR reagent kit. The relative abundance of mRNA was standardized with β-actin mRNA as the invariant control.
The lysates of kidney cortex tissues were subjected to SDS-PAGE and then electroblotted onto polyvinylidene difluoride (PVDF) membranes. Following the blocking step, the electroblotted membranes were immunoblotted with the primary antibodies against a-SMA, TIMP1, a-tublin respectively. The membranes immunoblotted were incubated with horseradish peroxidase-labelled secondary antibodies. After washing, the membranes were exposed to X-ray film. The bands of resulting autoradiographs were quantified densitometrically using Bandscan software.
2. The synchronized MES-13cells were assigned to six groups:(1) NG, medium containing normal glucose concentration (-5.6mmol/L);(2) HG, medium containing25mmol/L glucose;(3) AKF-PD, medium containing HG and400μg/mL AKF-PD;(4) PFD, medium containing HG and400μg/mL pirfenidone;(5) Los, medium containing HG and2μmol/L losartan;(6) OC, medium containing NG and19.4mmol/L mannitol as an osmotic control. The cells in all six groups were cultured for72h, and then cells and culture supernatants were collected for RT-PCR and Western blotting.
TGF-β1protein levels in supernatants from MES-13cell cultures were determined by using a TGF-β1ELISA kit.
Total RNA was isolated from MES-13cells. The cDNA was synthesized from total RNA. RT-PCR primers for α1(Ⅰ)collagen, al(IV)collagen, fibronectin, TGF-β1, tissue inhibitors-1of metalloproteinases (TIMP-1), cc-smooth muscle actin (a-SMA) and β-actin were ordered from Sangon Inc. Amplification reactions were performed in duplicate with SYBR Green PCR reagent kit. The relative abundance of mRNA was standardized with β-actin mRNA as the invariant control.
The lysates of MES-13cells were subjected to SDS-PAGE and then electroblotted onto polyvinylidene difluoride (PVDF) membranes. Following the blocking step, the electroblotted membranes were immunoblotted with the primary antibodies against a-SMA, TIMP1, a-tublin respectively. The membranes immunoblotted were incubated with horseradish peroxidase-labelled secondary antibodies. After washing, the membranes were exposed to X-ray film. The bands of resulting autoradiographs were quantified densitometrically using Bandscan software.
Results
Kidney weights of diabetic db/db mice were markedly greater than those of dblm mice(P<0.05). Treatment with AKF-PD reduced the kidney hypertrophy of diabetic dbldb mice, as indicated by decreased kidney weight and kidney/body weight ratio in treated dbldb mice compared with untreated dbldb mice. The diminished effect of AKF-PD on the renal hypertrophy was most obvious at a dosage of500mg/kg body weight per day(P<0.01).
Diabetic db/db mice had heavy albuminuria. The urinary albumin excretion rate was higher by8-fold in dbldb mice than that in dblm mice group(P<0.01). The administration of AKF-PD significantly attenuated albuminuria of diabetic db/db mice and a dose of500mg/kg body weight was the peak-effective dose at which24-h urinary albumin excretion declined by58.5percent(P<0.01).
The dbldb mice remained hyperglycemic throughout the experimental period, and their mean blood glucose levels were about5times as high as in dblm mice(P<0.01). No significant differences of blood glucose were observed between AKF-PD treated and untreated dbldb mice groups.
In comparison with dblm mice, PAS-positive mesangial matrix areas were substantially enlarged and the glomerular mesangial expansion index (GMI) i.e., the ratio of mesangial matrix area divided by the tuft area, was significantly increased in dbldb mice(P<0.01). Compared with untreated dbldb mice group, the PAS-positive mesangial matrix areas and GMIs decreased obviously in AKF-PD-treated dbldb mice groups(P<0.05) and GMI was reduced by approximately55.8%at the dose of500mg/kg body weight(P<0.01).
The mRNA levels of α1(Ⅰ)collagen, α1(Ⅳ)collagen and fibronectin in renal cortex of db/db mice were3-4times higher than those in dblm mice(P<0.01). The up-regulated expressions of the three ECM components at the transcriptional level were dose-dependently reduced in renal cortex of diabetic dbldb mice subjected to AKF-PD treatment(P<0.05).
Diabetic db/db mice had the marked upregulation of expression TGF-β1mRNA and protein in renal cortex compared with dblm mice(P<0.01). AKF-PD treatment reduced significantly the enhanced expression of TGF-(31mRNA and protein in dbldb mice(P<0.05).
Compared with dblm mice, expression of renal cortex TIMP-1was markedly upregulated in diabetic dbldb mice as indicated by real-time RT-PCR and western blotting(P<0.01). The upregulated renal expressions of TIMP-1mRNA and protein in dbldb mice were significantly inhibited by AKF-PD treatment(P<0.01).
The mRNA and protein expressions of a-SMA in renal cortex of diabetic dbldb mice were markedly upregulated compared with dblm mice(P<0.01). AKF-PD administration to dbldb mice inhibited dramatically the upregulated expressions of a-SMA mRNA and protein in renal cortex(P<0.05), and the maximally effective doses were about500mg/kg body weight per day.
The expression of α1(Ⅰ) and α1(Ⅳ) collagen mRNAs in HG group of MES-13cells was obviously increased compared with NG group(P<0.01). The addition of AKF-PD, PFD or losartan to culture media inhibited significantly the high glucose-induced upregulation of α1(Ⅰ) and α1(Ⅳ) collagen mRNA expression in mesangial cells(P<0.05), and there was no significant difference among the three agents.
Each of AKF-PD, PFD and losartan can inhibit significantly the up-regulated expression of TGF-β1mRNA induced by high glucose in MES-13cells in vitro(P<0.01), and differences between the three agents were not statistically significant. AKF-PD, PFD and losartan also inhibit significantly the high glucose-stimulated upregulation of TGF-β1protein expression in the cultured mesangial cells(P<0.05). However, both AKF-PD and PFD can reverse the expression of TGF-β1protein approximately to the level of NG group, but this inhibitory effect of losartan seemed to be slightly weaker.
Both mRNA and protein expression of TIMP-1by cultured mesangial cells were remarkably increased in HG group compared with the NG group (P<0.01). The levels of TIMP-1mRNA and protein in the AKF-PD-, PFD-and losartan-treatment groups were obviously lower than those in HG group(P<0.01). No significant difference in TIMP-1was observed among these three treatment groups.
In comparison with NG group, the expression level of a-SMA protein in HG group was significantly higher(P<0.01). The addition of AKF-PD, PFD or losartan to the culture media significantly inhibited the expression of a-SMA protein by cultured mesangial cells under high glucose conditions(P<0.05). The differences in a-SMA protein expression among these three agents were not significant.
Conclusion
This study demonstrates that long-term administration of AKF-PD attenuates renal hypertrophy, mesangial matrix expansion and albuminuria in the diabetic db/db mice despite continued hyperglycemia. Upregulated expressions of several ECM components, TIMP-1, TGF-β1and a-SMA at the transcriptional and protein levels are significantly inhibited by AKF-PD treatment in renal cortex of db/db mice and cultured mesangial cells under high glucose conditions. The results presented here suggest that AKF-PD is able to ameliorate the ECM production and degradation imbalance via the inhibition of TGF-β1pathway, resulting in attenuation of renal fibrosis associated with diabetic state. Therefore, use of AKF-PD as a potent antifibrotic agent holds great promise for the therapy of diabetic nephropathy.
引文
[1]Reutens AT, Atkins RC. Epidemiology of diabetic nephropathy. Contrib Nephrol,2011; 170:1-7.
[2]Ning G, Hong J, Bi Y, et al. Progress in diabetes research in China. J Diabetes,2009; 1:163-172.
[3]Rossing P, de Zeeuw D. Need for better diabetes treatment for improved renal outcome. Kidney Int Suppl,2011; 120:S28-32.
[4]Fioretto P, Mauer M. Histopathology of diabetic nephropathy. Semin Nephrol,2007; 27(2):195-207.
[5]Kamenetsky I, Rangayyan RM, Benediktsson H. Analysis of the glomerular basement membrane in images of renal biopsies using the split-and-merge method:a pilot study. J Digit Imaging,2010; 23(4):463-474.
[6]Ayodele OE, Alebiosu CO, Salako BL. Diabetic nephropathy-a review of the natural history, burden, risk factors and treatment. J Natl Med Assoc, 2004; 96(11):1445-1454.
[7]Blazquez-Medela AM, Lopez-Novoa JM, Martinez-Salgado C. Mechanisms involved in the genesis of diabetic nephropathy. Curr Diabetes Rev,2010; 6(2):68-87.
[8]Kashihara N, Haruna Y, Kondeti VK, et al. Oxidative stress in diabetic nephropathy. Curr Med Chem.2010;17(34):4256-4269.
[9]Daroux M, Prevost G, Maillard-Lefebvre H, et al. Advanced glycation end-products:implications for diabetic and non-diabetic nephropathies. Diabetes Metab,2010; 36(1):1-10.
[10]Min D, Lyons JG, Bonner J, et al. Mesangial cell-derived factors alter monocyte activation and function through inflammatory pathways: possible pathogenic role in diabetic nephropathy. Am J Physiol Renal Physiol,2009; 297(5):F 1229-237.
[11]Chawla T, Sharma D, Singh A. Role of the renin angiotensin system in diabetic nephropathy. World J Diabetes,2010; 1(5):141-145.
[12]Gnudi L, Thomas SM, Viberti G. Mechanical forces in diabetic kidney disease:a trigger for impaired glucose metabolism. J Am Soc Nephrol, 2007; 18:2226-2232.
[13]Ban CR, Twigg SM. Fibrosis in diabetes complications:pathogenic mechanisms and circulating and urinary markers. Vasc Health Risk Manag, 2008; 4(3):575-596.
[14]Thrailkill KM, Clay Bunn R, Fowlkes JL. Matrix metalloproteinases:their potential role in the pathogenesis of diabetic nephropathy. Endocrine, 2009; 35(1):1-10.
[15]Skill NJ, Griffin M, El Nahas AM, et al. Increases in renal epsilon-(gamma-glutamyl)-lysine crosslinks result from compartment-specific changes in tissue transglutaminase in early experimental diabetic nephropathy:pathologic implications. Lab Invest, 2001; 81(5):705-716.
[16]Choudhury D, Tuncel M, Levi M. Diabetic nephropathy-a multifaceted target of new therapies. Discov Med,2010; 10(54):406-415.
[17]Thomas MC, Groop PH. New approaches to the treatment of nephropathy in diabetes. Expert Opin Investig Drugs,2011; 20(8):1057-1071.
[18]Petersen M, Thorikay M, Deckers M, et al. Oral administration of GW788388, an inhibitor of TGF-beta type I and II receptor kinases, decreases renal fibrosis. Kidney Int,2008; 73:705-715.
[19]Li J, Kang SW, Kim JL, et al. Isoliquiritigenin entails blockade of TGF-beta1-SMAD signaling for retarding high glucose-induced mesangial matrix accumulation. J Agric Food Chem,2010; 58:3205-3212.
[20]Sugaru E, Nakagawa T, Ono-Kishino M, et al. SMP-534 ameliorates progression of glomerular fibrosis and urinary albumin in diabetic db/db mice. Am J Physiol Renal Physiol,2006; 290(4):F813-820.
[21]Hirano T, Kashiwazaki K, Moritomo Y, et al. Albuminuria is directly associated with increased plasma PAI-1 and factor VII levels in NIDDM patients. Diabetes Res Clin Pract,1997; 36(1):11-18.
[22]Richeldi L, Yasothan U, Kirkpatrick P. Pirfenidone. Nat Rev Drug Discov, 2011; 10(7):489-490.
[23]Iyer SN, Wild JS, Schiedt MJ, et al. Dietary intake of pirfenidone ameliorates bleomycin-induced lung fibrosis in hamsters. J Lab Clin Med, 1995; 125(6):779-785.
[24]Ramachandra Rao SP, Zhu Y, Ravasi T, et al. Pirfenidone is renoprotective in diabetic kidney disease. J Am Soc Nephrol,2009; 20(8): 1765-1775.
[25]Miric G, Dallemagne C, Endre Z, et al. Reversal of cardiac and renal fibrosis by pirfenidone and spironolactone in streptozotocin-diabetic rats. Br J Pharmacol,2001; 133(5):687-694.
[26]Shimizu T, Kuroda T, Hata S, et al. Pirfenidone improves renal function and fibrosis in the post-obstructed kidney. Kidney Int,1998; 54(1):99-109.
[27]Cho ME, Smith DC, Branton MH, et al. Pirfenidone slows renal function decline in patients with focal segmental glomerulosclerosis. Clin J Am Soc Nephrol,2007; 2(5):906-913.
[28]Lao LJ, Hu GY, Shi YE. Composition and method for treating fibrotic diseases:US 2009/0258911 A1[P].2009-10-15
[29]Yuan Q, Wang R, Peng Y, et al. Fluorofenidone attenuates tubulointerstitial fibrosis by inhibiting TGF-β(1)-induced fibroblast activation. Am J Nephrol,2011; 34(2):181-194.
[30]Li BX, Tang YT, Wang W, et al. Fluorofenidone attenuates renal interstitial fibrosis in the rat model of obstructive nephropathy. Mol Cell Biochem.2011; 354(1-2):263-273.
[31]Tao LJ, Zhang J, Hu GY. Effects of 1-(3-fluorophenyl)-5-methyl-2-(1H)-pyridone on renal fibroblast in rats. Zhong Nan Da Xue Xue Bao Yi Xue Ban,2004; 29(2):139-141.
[32]Peng ZZ, Hu GY, Shen H, et al. Fluorofenidone attenuates collagen I and transforming growth factor-betal expression through a nicotinamide adenine dinucleotide phosphate oxidase-dependent way in NRK-52E cells. Nephrology (Carlton),2009; 14(6):565-572.
[33]Wang L, Hu GY, Shen H, et al. Fluorofenidone inhibits TGF-betal induced CTGF via MAPK pathways in mouse mesangial cells. Pharmazie, 2009; 64(10):680-684.
[34]Sharma K, McCue P, Dunn SR. Diabetic kidney disease in the db/db mouse. Am J Physiol Renal Physiol,2003; 284(6):F1138-1144.
[35]Cohen MP, Lautenslager GT, Shearman CW. Increased urinary type Ⅳ collagen marks the development of glomerular pathology in diabetic d/db mice. Metabolism,2001; 50(12):1435-1440.
[36]Ziyadeh FN, Hoffman BB, Han DC, et al. Long-term prevention of renal insufficiency, excess matrix gene expression, and glomerular mesangial matrix expansion by treatment with monoclonal antitransforming growth factor-beta antibody in db/db diabetic mice. Proc Natl Acad Sci U S A, 2000; 97(14):8015-8020.
[37]Lim AK, Ma FY, Nikolic-Paterson DJ, et al. Antibody blockade of c-fms suppresses the progression of inflammation and injury in early diabetic nephropathy in obese db/db mice. Diabetologia,2009; 52(8):1669-1679.
[38]Fujii M, Inoguchi T, Sasaki S, et al. Bilirubin and biliverdin protect rodents against diabetic nephropathy by downregulating NAD(P)H oxidase. Kidney Int,2010; 78:905-919.
[39]Moriyama T, Oka K, Ueda H, Imai E. Nilvadipine attenuates mesangial expansion and glomerular hypertrophy in diabetic db/db mice, a model for type 2 diabetes. Clin Exp Nephrol,2004; 8:230-236.
[40]Cohen MP, Lautenslager GT, Hud E, et al. Inhibiting albumin glycation attenuates dysregulation of VEGFR-1 and collagen IV subchain production and the development of renal insufficiency. Am J Physiol Renal Physiol,2007; 292:F789-F795.
[41]Cao W, He L, Liu W, Huang Z, et al. Determination of AKF-PD in whole blood of rat by HPLC-UV. J Chromatogr B Analyt Technol Biomed Life Sci 2006; 833:257-259.
[42]Cohen MP, Sharma K, Jin Y, et al. Prevention of diabetic nephropathy in db/db mice with glycated albumin antagonists. A novel treatment strategy. J Clin Invest,1995; 95(5):2338-2345.
[43]Hong SW, Isono M, Chen S, et al. Increased glomerular and tubular expression of transforming growth factor-beta1, its type II receptor, and activation of the Smad signaling pathway in the db/db mouse. Am J Pathol, 2001;158(5):1653-1663.
[44]Mauer SM, Steffes MW, Ellis EN, et al.Structural-functional relationships in diabetic nephropathy. J Clin Invest 1984; 74(4):1143-1155.
[45]Steffes MW, Osterby R, Chavers B, et al. Mesangial expansion as a central mechanism for loss of kidney function in diabetic patients. Diabetes.1989; 38(9):1077-1081.
[46]Moriya T, Tanaka K, Hosaka T, et al. Renal structure as an indicator for development of albuminuria in normo-and microalbuminuric type 2 diabetic patients. Diabetes Res Clin Pract.2008; 82(3):298-304.
[47]Menini S, Iacobini C, Oddi G, et al. Increased glomerular cell (podocyte) apoptosis in rats with streptozotocin-induced diabetes mellitus:role in the development of diabetic glomerular disease. Diabetologia,2007; 50(12):2591-2599.
[48]Rippe C, Rippe A, Torffvit O, et al. Size and charge selectivity of the glomerular filter in early experimental diabetes in rats. Am J Physiol Renal Physiol,2007; 293(5):F1533-538.
[49]Russo LM, Sandoval RM, Campos SB, et al. Impaired tubular uptake explains albuminuria in early diabetic nephropathy. J Am Soc Nephrol. 2009; 20(3):489-494.
[50]Tojo A, Onozato ML, Ha H, et al. Reduced albumin reabsorption in the proximal tubule of early-stage diabetic rats. Histochem Cell Biol,2001; 116(3):269-276.
[51]Chiarelli F, Verrotti A, Mohn A, et al. The importance of microalbuminuria as an indicator of incipient diabetic nephropathy: therapeutic implications. Ann Med,1997; 29(5):439-445.
[52]Kim MJ, Frankel AH, Donaldson M, et al. Oral cholecalciferol decreases albuminuria and urinary TGF-β1 in patients with type 2 diabetic nephropathy on established renin-angiotensin-aldosterone system inhibition. Kidney Int,2011; 80(8):851-860.
[53]Zhang H, Schin M, Saha J, et al. Podocyte-specific overexpression of GLUT1 surprisingly reduces mesangial matrix expansion in diabetic nephropathy in mice. Am J Physiol Renal Physiol,2010; 299(1):F91-98.
[54]Mason RM, Wahab NA. Extracellular matrix metabolism in diabetic nephropathy. J Am Soc Nephrol,2003; 14(5):1358-1373.
[55]Razzaque MS, Koji T, Taguchi T, et al. In situ localization of type III and type IV collagen-expressing cells in human diabetic nephropathy, J Pathol. 1994; 174(2):131-138.
[56]Suzuki D, Miyazaki M, Jinde K, et al 1. In situ hybridization studies of matrix metalloproteinase-3, tissue inhibitor of metalloproteinase-1 and type IV collagen in diabetic nephropathy. Kidney Int,1997; 52(1):111-119.
[57]Joladarashi D, Salimath PV, Chilkunda ND. Diabetes results in structural alteration of chondroitin sulfate/dermatan sulfate in the rat kidney:effects on the binding to extracellular matrix components. Glycobiology,2011; 21(7):960-972.
[58]Huang L, Haylor JL, Hau Z, et al 1. Transglutaminase inhibition ameliorates experimental diabetic nephropathy. Kidney Int,2009; 76(4):383-394.
[59]Brew K, Dinakarpandian D, Nagase H. Tissue inhibitors of metalloproteinases:evolution, structure and function. Biochim Biophys Acta,2000; 1477:267-283.
[60]Williams JM, Zhang J, North P, et al. Evaluation of metalloprotease inhibitors on hypertension and diabetic nephropathy. Am J Physiol Renal Physiol,2011; 300(4):F983-98.
[61]Ishimura E, Nishizawa Y, Shoji S, et al. Serum type III, IV collagens and TIMP in patients with type II diabetes mellitus. Life Sci,1996; 58(16):1331-1337.
[62]Rysz J, Banach M, Stolarek RA, et al. Serum matrix metalloproteinases MMP-2 and MMP-9 and metalloproteinase tissue inhibitors TIMP-1 and TIMP-2 in diabetic nephropathy. J Nephrol.2007; 20(4):444-452.
[63]Shankland SJ, Ly H, Thai K, et al. Glomerular expression of tissue inhibitor of metalloproteinase (TIMP-1) in normal and diabetic rats. J Am Soc Nephrol,1996; 7(1):97-104.
[64]Cruzado JM, Lloberas N, Torras J, et al. Regression of advanced diabetic nephropathy by hepatocyte growth factor gene therapy in rats. Diabetes, 2004; 53(4):1119-1127.
[65]Ito Y, Goldschmeding R, Kasuga H, et al. Expression patterns of connective tissue growth factor and of TGF-beta isoforms during glomerular injury recapitulate glomerulogenesis. Am J Physiol Renal Physiol,2010; 299(3):545-558.
[66]Yang Q, Xie RJ, Yang T, et al. Transforming growth factor-betal and Smad4 signaling pathway down-regulates renal extracellular matrix degradation in diabetic rats. Chin Med Sci J,2007; 22(4):243-249.
[67]Kondo T, Takemura G, Kosai K, et al. Application of an adenoviral vector encoding soluble transforming growth factor-beta type Ⅱ receptor to the treatment of diabetic nephropathy in mice. Clin Exp Pharmacol Physiol, 2008; 35(11):1288-1293.
[68]De Muro P, Faedda R, Fresu P, et al. Urinary transforming growth factor-beta 1 in various types of nephropathy. Pharmacol Res,2004; 49(3):293-298.
[69]Houlihan CA, Akdeniz A, Tsalamandris C, et al. Urinary transforming growth factor-beta excretion in patients with hypertension, type 2 diabetes, and elevated albumin excretion rate:effects of angiotensin receptor blockade and sodium restriction. Diabetes Care 2002; 25(6):1072-1077.
[70]Kolm-Litty V, Sauer U, Nerlich A, et al. High glucose-induced transforming growth factor betal production is mediated by the hexosamine pathway in porcine glomerular mesangial cells. J Clin Invest, 1998; 101(1):160-169.
[71]Qi W, Chen X, Poronnik P, et al. Transforming growth factor-beta/connective tissue growth factor axis in the kidney. Int J Biochem Cell Biol,2008;40(1):9-13.
[72]Wahab NA, Harper K, Mason RM. Expression of extracellular matrix molecules in human mesangial cells in response to prolonged hyperglycaemia. Biochem J,1996; 316 (Pt 3):985-892.
[73]Nakamura T, Miller D, Ruoslahti E, et al. Production of extracellular matrix by glomerular epithelial cells is regulated by transforming growth factor-beta 1. Kidney Int,1992; 41(5):1213-1221.
[74]Davies M, Thomas GJ, Martin J, et al. The purification and characterization of a glomerular-basement-membrane-degrading neutral proteinase from rat mesangial cells. Biochem J,1988; 251(2):419-425.
[75]Marti HP, Lee L, Kashgarian M, et al. Transforming growth factor-beta 1 stimulates glomerular mesangial cell synthesis of the 72-kd type IV collagenase. Am J Pathol,1994; 144(1):82-94.
[76]Weston BS, Wahab NA, Mason RM. CTGF mediates TGF-beta-induced fibronectin matrix deposition by upregulating active alpha5betal integrin in human mesangial cells. J Am Soc Nephrol,2003; 14(3):601-10.
[77]Hills CE, Squires PE. TGF-betal-induced epithelial-to-mesenchymal transition and therapeutic intervention in diabetic nephropathy. Am J Nephrol,2010; 31(1):68-74.
[78]Sharma K, Jin Y, Guo J, et al. Neutralization of TGF-beta by anti-TGF-beta antibody attenuates kidney hypertrophy and the enhanced extracellular matrix gene expression in STZ-induced diabetic mice. Diabetes,1996; 45(4):522-530.
[79]Meran S, Steadman R. Fibroblasts and myofibroblasts in renal fibrosis. Int J Exp Pathol,2011; 92(3):158-167.
[80]Humphreys BD, Lin SL, Kobayashi A, et al. Fate tracing reveals the pericyte and not epithelial origin of myofibroblasts in kidney fibrosis, Am J Pathol.2010; 176(1):85-97.
[81]Rastaldi MP, Ferrario F, Giardino L, et al. Epithelial-mesenchymal transition of tubular epithelial cells in human renal biopsies. Kidney Int, 2002;62(1):137-146.
[82]Li J, Qu X, Bertram JF. Endothelial-myofibroblast transition contributes to the early development of diabetic renal interstitial fibrosis in streptozotocin-induced diabetic mice. Am J Pathol,2009; 175(4):1380-1388.
[83]Ren X, Guan G, Liu G, et al. Irbesartan ameliorates diabetic nephropathy by reducing the expression of connective tissue growth factor and alpha-smooth-muscle actin in the tubulointerstitium of diabetic rats. Pharmacology,2009; 83(2):80-87.
[84]Ina K, Kitamura H, Tatsukawa S, et al. Significance of a-SMA in myofibroblasts emerging in renal tubulointerstitial fibrosis. Histol Histopathol.2011; 26(7):855-866.
[85]Lee S, Kim W, Moon SO, et al. Renoprotective effect of COMP-angiopoietin-1 in db/db mice with type 2 diabetes. Nephrol Dial Transplant 2007; 22(2):396-408.
[86]Benigni A, Zoja C, Coma D, et al. Add-on anti-TGF-beta antibody to ACE inhibitor arrests progressive diabetic nephropathy in the rat. J Am Soc Nephrol,2003;14(7):1816-24.
[87]Kensuke Asaba, Akihiro Tojo, Maristela Lika Onozato, et al. Effects of NADPH oxidase inhibitor in diabetic nephropathy. Kidney International, 2005;67(5):1890-1898.
[88]Simonson MS. Phenotypic transitions and fibrosis in diabetic nephropathy. Kidney Int,2007; 71(9):846-854.
[89]Chiang CK, Inagi R. Glomerular diseases:genetic causes and future therapeutics. Nat Rev Nephrol,2010;6(9):539-554.
[90]Ru Y, Song HM. Progress in the research on the role of mesangial remodeling in glomerualr diseases. Zhongguo Dang Dai Er Ke Za Zhi, 2009;11(10):866-868.
[91]Haneda M, Koya D, Isono M, et al. Overview of glucose signaling in mesangial cells in diabetic nephropathy. J Am Soc Nephrol,2003; 14: 1374-1382.
[92]Keeling J, Herrera GA. Human matrix metalloproteinases:characteristics and pathologic role in altering mesangial homeostasis. Microsc Res Tech, 2008; 71(5):371-379.
[93]Kanwar YS, Wada J, Sun L, et al. Diabetic nephropathy:mechanisms of renal disease progression. Exp Biol Med (Maywood),2008;233(1):4-11.
[94]Lee HS, Song CY. Differential role of mesangial cells and podocytes in TGF-beta-induced mesangial matrix synthesis in chronic glomerular disease. Histol Histopathol,2009 Jul;24(7):901-908.
[95]Gruden G, Perin PC, Camussi G. Insight on the pathogenesis of diabetic nephropathy from the study of podocyte and mesangial cell biology. Curr Diabetes Rev,2005;1(1):27-40.
[96]Yano N, Suzuki D, Endoh M, et al. High ambient glucose induces angiotensin-independent AT-1 receptor activation, leading to increases in proliferation and extracellular matrix accumulation in MES-13 mesangial cells. Biochem J,2009; 423:129-143.
[97]Matoba K, Kawanami D, Ishizawa S, et al. Rho-kinase mediates TNF-a-induced MCP-1 expression via p38 MAPK signaling pathway in mesangial cells. Biochem Biophys Res Commun,2010; 402(4):725-730.
[98]Lee MJ, Rao YK, Chen K, et al. Andrographolide and 14-deoxy-11,12-didehydroandrographolide from Andrographis paniculata attenuate high glucose-induced fibrosis and apoptosis in murine renal mesangeal cell lines. J Ethnopharmacol,2010;132(2):497-505.
[99]Davis LK, Rodgers BD, Kelley KM. Angiotensin Ⅱ-and glucose-stimulated extracellular matrix production:mediation by the insulin-like growth factor (IGF) axis in a murine mesangial cell line. Endocrine,2008;33(1):32-39.
[100]Cheng DW, Jiang Y, Shalev A, et al. An analysis of high glucose and glucosamine-induced gene expression and oxidative stress in renal mesangial cells. Arch Physiol Biochem,2006; 112(4-5):189-218.
[101]Jiang Y, Cheng DW, Crook ED, et al. Transforming growth factor-beta1 regulation of laminin gamma1 and fibronectin expression and survival of mouse mesangial cells. Mol Cell Biochem,2005;278(1-2):165-175.
[102]Sun J, Xu Y, Deng H, et al. Involvement of osteopontin upregulation on mesangial cells growth and collagen synthesis induced by intermittent high glucose. J Cell Biochem,2010;109(6):1210-21.
[103]Chin HJ, Fu YY, Ahn JM, et al. Omacor, n-3 polyunsaturated fatty acid, attenuated albuminuria and renal dysfunction with decrease of SREBP-1 expression and triglyceride amount in the kidney of type II diabetic animals. Nephrol Dial Transplant,2010;25(5):1450-1457.
[104]Schaeffer V, Hansen KM, Morris DR, et al. Reductions in laminin beta2 mRNA translation are responsible for impaired IGFBP-5-mediated mesangial cell migration in the presence of high glucose. Am J Physiol Renal Physiol,2010;298(2):314-322.
[105]Min D, Lyons JG, Bonner J, et al. Mesangial cell-derived factors alter monocyte activation and function through inflammatory pathways: possible pathogenic role in diabetic nephropathy. Am J Physiol Renal Physiol,2009;297(5):1229-1237.
[106]Taniguchi H, Ebina M, Kondoh Y, et al. Pirfenidone in idiopathic pulmonary fibrosis. Eur Respir J,.2010;35(4):821-829.
[107]Regulatory W, First drug for idiopathic pulmonary fibrosis approved in Japan Nat Rev Drug Discov,2008; 7:966-967.
[108]Armendariz-Borunda J, Islas-Carbajal MC, Meza-Garcia E, et al. A pilot study in patients with established advanced liver fibrosis using pirfenidone. Gut,2006; 55(11):1663-5.
[109]Cho ME, Smith DC, Branton MH, et al. Pirfenidone slows renal function decline in patients with focal segmental glomerulosclerosis. Clin J Am Soc Nephrol,2007; 2(5):876-878.
[110]Walker JE, Giri SN, Margolin SB. A double-blind, randomized, controlled study of oral pirfenidone for treatment of secondary progressive multiple sclerosis. Mult Scler,2005;11(2):149-158.
[111]Foley RN, Collins AJ. End-Stage Renal Disease in the United States:An Update from the United States Renal Data System. J Am Soc Nephrol, 2007;(18):2644-2648.
[112]Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med,2001;345:861-869.
[113]Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med,2001; 345:851-860.
[114]Wu D, Peng F, Zhang B, et al. EGFR-PLCgammal signaling mediates high glucose-induced PKCbetal-Akt activation and collagen I upregulation in mesangial cells. Am J Physiol Renal Physiol, 2009;297(3):822-834.
[115]Pozzi A, Zent R, Chetyrkin S, et al. Modification of collagen IV by glucose or methylglyoxal alters distinct mesangial cell functions. J Am Soc Nephrol.2009; 20(10):2119-2125.
[116]Baccora MH, Cortes P, Hassett C, et al. Effects of long-term elevated glucose on collagen formation by mesangial cells. Kidney Int, 2007;72(10):1216-1225.
[117]Giannico G, Cortes P, Baccora MH, et al. Glibenclamide prevents increased extracellular matrix formation induced by high glucose concentration in mesangial cells. Am J Physiol Renal Physiol,2007; 292(1):57-65.
[118]Pedchenko VK, Chetyrkin SV, Chuang P, et al. Mechanism of perturbation of integrin-mediated cell-matrix interactions by reactive carbonyl compounds and its implication for pathogenesis of diabetic nephropathy. Diabetes,2005; 54(10):2952-2960.
[119]Hayashida T, Schnaper HW. High ambient glucose enhances sensitivity to TGF-betal via extracellular signal--regulated kinase and protein kinase Cdelta activities in human mesangial cells. J Am Soc Nephrol, 2004;15(8):2032-2041.
[120]Li J, Lim SS, Lee ES, et al. Isoangustone A suppresses mesangial fibrosis and inflammation in human renal mesangial cells. Exp Biol Med (Maywood),2011;236(4):435-444.
[121]Xia L, Wang H, Munk S, et al. High glucose activates PKC-zeta and NADPH oxidase through autocrine TGF-betal signaling in mesangial cells. Am J Physiol Renal Physiol,2008;295(6):1705-1714.
[122]Simonson MS. Phenotypic transitions and fibrosis in diabetic nephropathy. Kidney Int,2007;71(9):846-854.
[123]Ziyadeh FN. Mediators of diabetic renal disease:the case for TGF-beta as the major mediator.J Am Soc Nephrol,2004;15 Suppl 1:55-57.
[124]Baricos WH, Cortez SL, Deboisblanc M, et al. Transforming growth factor-beta is a potent inhibitor of extracellular matrix degradation by cultured human mesangial cells. J Am Soc Nephrol,1999;10(4):790-795.
[125]Suzuki D, Miyazaki M, Jinde K, et al. In situ hybridization studies of matrix metalloproteinase-3, tissue inhibitor of metalloproteinase-1 and type IV collagen in diabetic nephropathy. Kidney Int,1997; 52(1):111-119.
[126]Shankland SJ, Ly H, Thai K, et al. Glomerular expression of tissue inhibitor of metalloproteinase (TIMP-1) in normal and diabetic rats. J Am Soc Nephrol,1996;7(1):97-104.
[127]Yang J, Zhou Q, Wang Y, et al. Effect of high glucose on PKC and MMPs/TIMPs in human mesangial cells. Zhong Nan Da Xue Xue Bao Yi Xue Ban,2009; 34(5):425-431.
[128]McLennan SV, Wang XY, Moreno V, et al. Connective tissue growth factor mediates high glucose effects on matrix degradation through tissue inhibitor of matrix metalloproteinase type 1:implications for diabetic nephropathy. Endocrinology,2004;145(12):5646-5655.
[1]Shaw JE, Sicree RA, Zimmet PZ. Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res Clin Pract,2010; 87(1):4-14.
[2]Xu L, Xie X, Wang S, et al. Prevalence of diabetes mellitus in China. Exp Clin Endocrinol Diabetes,2008; 116(1):69-70.
[3]Reutens AT, Atkins RC. Epidemiology of diabetic nephropathy. Contrib Nephrol,2011; 170:1-7.
[4]Kanwar YS, Sun L, Xie P, et al. A glimpse of various pathogenetic mechanisms of diabetic nephropathy. Annu Rev Pathol,2011; 6:395-423.
[5]Fioretto P, Mauer M. Histopathology of diabetic nephropathy. Semin Nephrol. 2007; 27(2):195-207.
[6]Choudhury D, Tuncel M, Levi M. Diabetic nephropathy-a multifaceted target of new therapies. Discov Med,2010; 10(54):406-415.
[7]Ayodele OE, Alebiosu CO, Salako BL. Diabetic nephropathy-a review of the natural history, burden, risk factors and treatment. J Natl Med Assoc,2004; 96(11):1445-1454.
[8]Rossing P, de Zeeuw D. Need for better diabetes treatment for improved renal outcome. Kidney Int Suppl,2011; 120:S28-32.
[9]Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature,2001; 414(6865):813-820.
[10]The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes. N Engl J Med,1993; 329(14):977-986.
[11]UK Prospective Diabetes Study (UKPDS) Group. Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet, 1998; 352(9131):837-853.
[12]Writing Team for the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Sustained effect of intensive treatment of type 1 diabetes mellitus on development and progression of diabetic nephropathy:the Epidemiology of Diabetes Interventions and Complications (EDIC) study. JAMA,2003; 290(16):2159-2167.
[13]Holman RR, Paul SK, Bethel MA, et al.10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med,2008; 359(15):1577-1589.
[14]ADVANCE Collaborative Group, Patel A, MacMahon S, Chalmers J et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med,2008; 358(24):2560-2572.
[15]Raskin P, Allen E, Hollander P, et al. Initiating insulin therapy in type 2 Diabetes:a comparison of biphasic and basal insulin analogs. Diabetes Care, 2005; 28(2):260-265.
[16]Rodbard HW, Jellinger PS, Davidson JA, et al. Statement by an American Association of Clinical Endocrinologists/American College of Endocrinology consensus panel on type 2 diabetes mellitus:an algorithm for glycemic control. Endocr Pract,2009; 15(6):540-559.
[17]The DCCT Research Group. Effect of intensive therapy on the development and progression of diabetic nephropathy in the Diabetes Control and Complications Trial. Kidney Int,1995; 47(6):1702-1720.
[18]The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. N Engl J Med,2000; 342(6):381-389.
[19]Stenvinkel P, Bolinder J, Alvestrand A. Effects of insulin on renal haemodynamics and the proximal and distal tubular sodium handling in healthy subjects. Diabetologia,1992; 35(11):1042-1048.
[20]Rabkin R, Ryan MP, Duckworth WC. The renal metabolism of insulin. Diabetologia,1984; 27(3):351-357.
[21]RaveK, Heise T, Pfutzner A, et al. Impact of diabetic nephropathy on pharmacodynamic and pharmacokinetic properties of insulin in type 1 diabetic patients. Diabetes Care,2001; 24(5):886-890.
[22]BiesenbachG, Raml A, Schmekal B, et al. Decreased insulin requirement in relation to GFR in nephropathic Type 1 and insulin-treated Type 2 diabetic patients. Diabet Med,2003; 20(8):642-645,
[23]Mak RH. Impact of end-stage renal disease and dialysis on glycemic control. Semin Dial,2000; 13(1):4-8.
[24]Reilly JB, Berns JS. Selection and dosing of medications for management of diabetes in patients with advanced kidney disease. Semin Dial,2010; 23(2):163-168.
[25]Mitrakou A. Kidney:its impact on glucose homeostasis and hormonal regulation. Diabetes Res Clin Pract,2011; 93 Suppl 1:S66-72.
[26]Sheldon B, Russell-Jones D, Wright J. Insulin analogues:an example of applied medical science. Diabetes Obes Metab.2009; 11(1):5-19.
[27]Iglesias P, Diez JJ. Insulin therapy in renal disease. Diabetes Obes Metab,2008; 10(10):811-823.
[28]Lyness W, Tyler JF. Lawrence A. Renal impairment does not affect insulin aspart pharmacokinetics in type 1 diabetes. Diabetes,2001; 50 (Suppl.2): A441-A442.
[29]Ciardullo AV, Bacchelli M, Daghio MM, et al. Effectiveness and safety of insulin glargine in the therapy of complicated or secondary diabetes:clinical audit. Acta Diabetol,2006; 43(2):57-60.
[30]Ersoy A, Ersoy C, Altinay T. Insulin analogue usage in a haemodialysis patient with type 2 diabetes mellitus. Nephrol Dial Transplant,2006; 21(2):553-554.
[31]Cavanaugh KL. Diabetes management issues for patients with chronic kidney disease. Clinical Diabetes,2007; 25(3):90-97.
[32]Haneda M, Morikawa A. Which hypoglycaemic agents to use in type 2 diabetic subjects with CKD and how? Nephrol Dial Transplant,2009; 24(2):338-341.
[33]Hasslacher C. Safety and efficacy of repaglinide in type 2 diabetic patients with and without impaired renal function. Diabetes Care,2003; 26(3):886-891.
[34]Sarafidis PA, Stafylas PC, Georgianos PI, et al. Effect of thiazolidinediones on albuminuria and proteinuria in diabetes:a meta-analysis. Am J Kidney Dis, 2010; 55(5):835-847.
[35]Bailey CJ,Turner RC. Metformin. N Engl J Med,1996; 334(9):574-579.
[36]Reilly JB, Berns JS. Selection and dosing of medications for management of diabetes in patients with advanced kidney disease. Semin Dial,2010; 23(2):163-168.
[37]Davidson JA. Incorporating incretin-based therapies into clinical practice: differences between glucagon-like Peptide 1 receptor agonists and dipeptidyl peptidase 4 inhibitors. Mayo Clin Proc,2010; 85(12 Suppl):S27-37.
[38]Kodera R, Shikata K, Kataoka HU, et al. Glucagon-like peptide-1 receptor agonist ameliorates renal injury through its anti-inflammatory action without lowering blood glucose level in a rat model of type 1 diabetes. Diabetologia, 2011;54(4):965-978.
[39]Ishibashi Y, Nishino Y, Matsui T, et al. Glucagon-like peptide-1 suppresses advanced glycation end product-induced monocyte chemoattractant protein-1 expression in mesangial cells by reducing advanced glycation end product receptor level. Metabolism,2011; 60(9):1271-1277.
[40]Liu WJ, Xie SH, Liu YN, et al. Dipeptidyl peptidase (DPP) IV inhibitor attenuates kidney injury in streptozotocin induced diabetic rats. J Pharmacol Exp Ther,2012; 340(2):248-255.
[41]Park CW, Kim HW, Ko SH, et al. Long-term treatment of glucagon-like peptide-1 analog exendin-4 ameliorates diabetic nephropathy through improving metabolic anomalies in db/db mice. J Am Soc Nephrol,2007; 18(4):1227-1238.
[42]Jacobsen LV, Hindsberger C. Robson R, et al. Effect of renal impairment on the pharmaco-kinetics of the GLP-1 analogue liraglutide. Br J Clin Pharmacol, 2009; 68(6):898-905.
[43]Chao EC, Henry RR. SGLT2 inhibition-a novel strategy for diabetes treatment. Nat Rev Drug Discov,2010; 9(7):551-559.
[44]Vallon V, Sharma K. Sodium-glucose transport:role in diabetes mellitus and potential clinical implications. Curr Opin Nephrol Hypertens,2010; 19(5):425-431.
[45]Han S, Hagan DL, Taylor JR, et al. Dapagliflozin, a selective SGLT2 inhibitor, improves glucose homeostasis in normal and diabetic rats. Diabetes,2008; 57(6):1723-1729.
[46]List JF, Woo V, Morales E et al 1. Sodium-glucose cotransport inhibition with dapagliflozin in type 2 diabetes. Diabetes Care,2009; 32(4):650-657.
[47]Bailey CJ, Gross JL, Pieters A, et al. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin:a randomized, double-blind, placebo-controlled trial. Lancet,2010; 375(9733):2223-2233.
[48]48. Tarnow L, Rossing P, Gall MA, et al. Prevalence of arterial hypertension in diabetic patients before and after the JNC-V. Diabetes Care,1994; 17(11): 1247-1251.
[49]Van Buren PN, Toto R. Hypertension in diabetic nephropathy:epidemiology, mechanisms, and management. Adv Chronic Kidney Dis,2011; 18(1):28-41.
[50]Chawla T, Sharma D, Singh A. Role of the renin angiotensin system in diabetic nephropathy. World J Diabetes,2010; 1(5):141-145.
[51]Gnudi L, Thomas SM, Viberti G. Mechanical forces in diabetic kidney disease: a trigger for impaired glucose metabolism. J Am Soc Nephrol,2007; 18:2226-2232.
[52]Mogensen CE. Progression of nephropathy in long-term diabetics with proteinuria and effect of initial anti-hypertensive treatment. Scand J Clin Lab Invest,1976; 36:383-388.
[53]Kasiske BL, Kalil RS, Ma JZ, et al. Effect of antihypertensive therapy on the kidney in patients with diabetes:a meta-regression analysis. Ann Intern Med, 1993; 118(2):129-138.
[54]Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med,2001; 345(12):851-860.
[55]Lewis EJ, Hunsicker LG, Bain RP, et al. The effect of angiotensin converting enzyme inhibition on diabetic nephropathy. N Engl J Med,329(20):1456-1462.
[56]Kvetny J, Gregersen G, Pedersen RS. Randomized placebo-controlled trial of perindopril in normotensive, normoalbuminuric patients with type 1 diabetes mellitus. QJM.2001; 94(2):89-94.
[57]Viberti G, Wheeldon NM. Microalbuminuria reduction with valsartan in patients with type 2 diabetes mellitus:a blood pressure-independent effect. Circulation,2002; 106(6):672-678.
[58]Thurman JM, Schrier RW. Comparative effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on blood pressure and the kidney. Am J Med,2003; 114(7):588-598.
[59]Shammas NW, Sica DA, Toth PP. A guide to the management of blood pressure in the diabetic hypertensive patient. Am J Cardiovasc Drugs,2009; 9(3):149-162.
[60]Mogensen CE, Neldam S, Tikkanen I, et al. Randomised controlled trial of dual blockade of renin-angiotensin system in patients with hypertension, microalbuminuria, and non-insulin dependent diabetes:the candesartan and lisinopril microalbuminuria (CALM) study. BMJ,2000; 321(7274):1440-1444.
[61]Jacobsen P, Rossing K, Parving HH. Single versus dual blockade of the renin-angiotensin system (angiotensin-converting enzyme inhibitors and/or angiotensin Ⅱ receptor blockers) in diabetic nephropathy. Curr Opin Nephrol Hypertens,2004; 13(3):319-324.
[62]Sato A, Hayashi K, Naruse M, et al. Effectiveness of aldosterone blockade in patients with diabetic nephropathy. Hypertension,2003; 41(1):64-68.
[63]Daugherty KK. Aliskiren. Am J Health Syst Pharm,2008; 65(14):1323-1332.
[64]Miiller DN, Luft FC. Direct renin inhibition with aliskiren in hypertension and target organ damage.Clin J Am Soc Nephrol,2006; 1(2):221-228.
[65]Kelly DJ, Zhang Y, Moe G, et al. Aliskiren, a novel renin inhibitor, is renoprotective in a model of advanced diabetic nephropathy in rats. Diabetologia,2007; 50(11):2398-2404.
[66]Phillips LM, Wang Y, Dai T, et al. The renin inhibitor aliskiren attenuates high-glucose induced extracellular matrix synthesis and prevents apoptosis in cultured podocytes. Nephron Exp Nephrol,2011; 118(3):e49-59.
[67]Persson F, Rossing P, Schjoedt KJ, et al. Time course of the antiproteinuric and anti-hypertensive effects of direct renin inhibition in type 2 diabetes. Kidney Int,2008; 73(12):1419-1425.
[68]Persson F, Lewis JB, Lewis EJ, et al. Impact of baseline renal function on the efficacy and safety of aliskiren added to losartan in patients with type 2 diabetes and nephropathy. Diabetes Care,2010; 33(11):2304-2309.
[69]Persson F, Lewis JB, Lewis EJ, et al. Aliskiren in combination with losartan reduces albuminuria independent of baseline blood pressure in patients with type 2 diabetes and nephropathy. Clin J Am Soc Nephrol,2011; 6(5):1025-1031.
[70]Yusuf S, Teo KK, Pogue J, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med,2008; 358(15):1547-1559.
[71]Zhang D, Gu T, Forsberg E, et al. Genetic and functional effects of membrane metallo-endopeptidase on diabetic nephropathy development. Am J Nephrol, 2011;34(5):483-490.
[72]Quaschning T. Vasopeptidase inhibition for blood pressure control:emerging experience. Curr Pharm Des,2005;11(25):3293-3299.
[73]Houlihan CA, Allen TJ, Baxter AL et al. A low-sodium diet potentiates the effects of losartan in type 2 diabetes. Diabetes Care,2002; 25(4):663-671.
[74]Taal MW, Nenov VD, Wong W, et al. Vasopeptidase inhibition affords greater renoprotection than angiotensin-converting enzyme inhibition alone. J Am Soc Nephrol,2001; 12(10):2051-2059.
[75]Russell JC, Kelly SE, Schafer S. Vasopeptidase inhibition improves insulin sensitivity and endothelial function in the JCR:LA-cp rat. J Cardiovasc Pharmacol,2004; 44(2):258-265.
[76]Davis BJ, Johnston CI, Burrell LM, et al. Renoprotective effects of vasopeptidase inhibition in an experimental model of diabetic nephropathy. Diabetologia,2003; 46(7):961-971.
[77]Cheng ZJ, Gronholm T, Louhelainen M, et al. Vascular and renal effects of vasopeptidase inhibition and angiotensin-converting enzyme blockade in spontaneously diabetic Goto-Kakizaki rats. J Hypertens,2005; 23(9):1757-1770.
[78]Fredersdorf S, Weil J, Ulucan C, et al. Vasopeptidase inhibition attenuates proteinuria and podocyte injury in Zucker diabetic fatty rats. Naunyn Schmiedebergs Arch Pharmacol,2007; 375(2):95-103.
[79]Schafer S, Linz W, Bube A, et al. Vasopeptidase inhibition prevents nephropathy in Zucker diabetic fatty rats. Cardiovasc Res,2003; 60(2):447-454.
[80]Portero-Otin M, Pamplona R, Boada J, et al. Inhibition of renin angiotensin system decreases renal protein oxidative damage in diabetic rats. Biochem Biophys Res Commun,2008; 368(3):528-535.
[81]Gross O, Koepke ML, Beirowski B, et al. Nephroprotection by antifibrotic and anti-inflammatory effects of the vasopeptidase inhibitor AVE7688. Kidney Int, 2005; 68(2):456-463.
[82]Tikkanen T, Tikkanen I, Rockell MD, et al. Dual inhibition of neutral endopeptidase and angiotensin-converting enzyme in rats with hypertension and diabetes mellitus. Hypertension,1998; 32(4):778-785.
[83]Azizi M, Bissery A, Peyrard S, et al. Pharmacokinetics and pharmacodynamics of the vasopeptidase inhibitor AVE7688 in humans. Clin Pharmacol Ther,2006; 79(1):49-61.
[84]Rousso P, Buclin T, Nussberger J, et al. Effects of a dual inhibitor of angiotensin converting enzyme and neutral endopeptidase, MDL 100,240, on endocrine and renal functions in healthy volunteers. J Hypertens,1999; 17(3):427-437.
[85]Liao WC, Vesterqvist O, Delaney C, et al. Pharmacokinetics and pharmacodynamics of the vasopeptidase inhibitor, omapatrilat in healthy subjects. Br J Clin Pharmacol,2003; 56(4):395-406.
[86]Regamey F, Maillard M, Nussberger J, et al. Renal hemodynamic and natriuretic effects of concomitant Angiotensin-converting enzyme and neutral endopeptidase inhibition in men. Hypertension,2002; 40(3):266-272.
[87]Azizi M, Lamarre-Cliche M, Labatide-Alanore A, et al. Physiologic consequences of vasopeptidase inhibition in humans:effect of sodium intake. J Am Soc Nephrol,2002; 13(10):2454-2463.
[88]Liao W, Delaney CL, Catanzariti PA, et al. Omapatrilat is not a diuretic: single-and multipledose analysis of the urinary excretion of sodium. Am J Hypertens,2000; 13:133A(abstract).
[89]Campese VM, Lasseter KC, Ferrario CM et al. Omapatrilat versus lisinopril: efficacy and neurohormonal profile in saltsensitive hypertensive patients. Hypertension,2000; 38(6):1342-1348.
[90]Kostis JB, Packer M, Black HR et al. Omapatrilat and enalapril in patients with hypertension:the Omapatrilat Cardiovascular Treatment vs. Enalapril (OCTAVE) trial. Am J Hypertens,2004; 17:103-111.
[91]Dimitropoulos N, Papakyriakou A, Dalkas GA, et al. A computational approach to the study of the binding mode of dual ACE/NEP inhibitors. J Chem Inf Model,2010; 50(3):388-396.
[92]Maahs DM, Ogden LG, Dabelea D, et al. Association of glycaemia with lipids in adults with type 1 diabetes:modification by dyslipidaemia medication. Diabetologia,2010; 53(12):2518-2525.
[93]Bell DS, Al Badarin F, O'Keefe JH Jr. Therapies for diabetic dyslipidaemia. Diabetes Obes Metab.2011; 13(4):313-325.
[94]Mazzone T, Chait A, Plutzky J. Cardiovascular disease risk in type 2 diabetes mellitus:insights from mechanistic studies. Lancet,2008; 371(9626):1800-1819.
[95]Moorhead JF, Chan MK, El-Nahas M, et al. Lipid nephrotoxicity in chronic progressive glomerular and tubulointerstitial disease. Lancet,1982; 320(8311):1309-1311.
[96]Ravid M, Brosh D, Ravid-Safran D, et al. Main risk factors for nephropathy in type 2 diabetes mellitus are plasma cholesterol levels, mean blood pressure, and hyperglycemia. Arch Intern Med,1998; 158(9):998-1004.
[97]Palmer BE, Alpern RJ. Treating dyslipidemia to slow the progression of chronic renal failure. Am J Med,2003; 114(5):411-412.
[98]Eddy AA, Liu E, McCulloch L. Interstitial fibrosis in hypercholesterolemic rats: role of oxidation, matrix synthesis, and proteolytic cascades. Kidney Int,1998; 53(5):1182-1189.
[99]Pai R, Kirschenbaum MA, Kamanna VS. Low-density lipoprotein stimulates the expression of macrophage colony-stimulating factor in glomerular mesangial cells. Kidney Int,1995; 48(4):1254-1262.
[100]Haffner SM. Statin therapy for the treatment of diabetic dyslipidemia. Diabetes Metab Res Rev,2003; 19(4):280-287.
[101]Fellstrom, BC, Jardine AG, Schmieder RE, et al. Rosuvastatin and cardiovascular events in patients undergoing hemodialysis. N Engl J Med,2009; 360(14):1395-1407.
[102]Tonelli M, Moye L, Sacks FM, et al. Cholesterol and Recurrent Events (CARE) Trial Investigators. Pravastatin for secondary prevention of cardiovascular events in persons with mild chronic renal insufficiency. Ann Intern Med,2003; 138(2):98-104.
[103]Kostapanos MS, Liberopoulos EN, Elisaf MS. Statin pleiotropy against renal injury. J Cardiometab Syndr.2009; 4(1):E4-9.
[104]Usui H, Shikata K, Matsuda M, et al. HMG-CoA reductase inhibitor ameliorates diabetic nephropathy by its pleiotropic effects in rats. Nephrol Dial Transplant,2003; 18(2):265-272.
[105]Wei P, Grimm PR, Settles DC, et al. Simvastatin reverses podocyte injury but not mesangial expansion in early stage type 2 diabetes mellitus. Ren Fail,2009; 31(6):503-513.
[106]Tamura Y, Murayama T, Minami M, et al. Differential effect of statins on diabetic nephropathy in db/db mice. Int J Mol Med,2011; 28(5):683-687.
[107]Abe M, Maruyama N, Okada K, et al. Effects of lipid-lowering therapy with rosuvastatin on kidney function and oxidative stress in patients with diabetic nephropathy. J Atheroscler Thromb,2011; 18(11):1018-1028.
[108]Danesh FR, Kanwar YS. Modulatory effects of HMG-CoA reductase inhibitors in diabetic microangiopathy. FASEB J,2004; 18(7):805-815.
[109]Sandhu S, Wiebe N, Fried LF, et al. Statins for improving renal outcomes:a metaanalysis. J Am Soc Nephrol,2006; 17(7):2006-2016.
[110]Colhoun HM, Betteridge DJ, Durrington PN, et al. Effects of atorvastatin on kidney outcomes and cardiovascular disease in patients with diabetes:an analysis from the Collaborative Atorvastatin Diabetes Study (CARDS). Am J Kidney Dis,2009; 54(5):810-819.
[111]Keating GM. Fenofibrate. A review of its lipid-modifying effects in dyslipidemia and its vascular effects in type 2 diabetes mellitus. Am J Cardiovasc Drugs,2011;11(4):227-247.
[112]Park CW, Zhang Y, Zhang X, et al. PPARalpha agonist fenofibrate improves diabetic nephropathy in db/db mice. Kidney Int,2006; 69(9):1511-1517.
[113]Li L, Emmett N, Mann D, et al. Fenofibrate attenuates tubulointerstitial fibrosis and inflammation through suppression of nuclear factor-KB and transforming growth factor-β1/Smad3 in diabetic nephropathy. Exp Biol Med (Maywood), 2010; 235(3):383-391.
[114]Tanaka Y, Kume S, Araki S, et al. Fenofibrate, a PPARa agonist, has renoprotective effects in mice by enhancing renal lipolysis. Kidney Int.2011; 79(8):871-882.
[115]Ansquer JC, Foucher C, Rattier S, et al; DAIS Investigators. Fenofibrate reduces progression to microalbuminuria over 3 years in a placebo-controlled study in type 2 diabetes:results from the Diabetes Atherosclerosis Intervention Study (DAIS). Am J Kidney Dis,2005; 45(3):485-493.
[116]The FIELD Study Investigators. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (The FIELD study):randomised controlled trial. Lancet,2005; 366(3):1849-1861.
[117]Davis TM, Ting R, Best JD, et al. FIELD Study investigators. Effects of fenofibrate on renal function in patients with type 2 diabetes mellitus:the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study. Diabetologia,2011; 54(2):280-290.
[118]Forsblom C, Hiukka A, Leinonen ES, et al. Effects of long-term fenofibrate treatment on markers of renal function in type 2 diabetes:the FIELD Helsinki substudy. Diabetes Care,2010; 33(2):215-220.
[119]Ginsberg HN, Elam MB, Lovato LC, et al. Effects of Combination Lipid Therapy in Type 2 Diabetes Mellitus. N Engl J Med,2010; 362(17):1563-1574.
[120]Farnier M, Steinmetz A, Retterst(?)l K, et al. Fixed-dose combination fenofibrate/pravastatin 160/40 mg versus simvastatin 20 mg monotherapy in adults with type 2 diabetes and mixed hyperlipidemia uncontrolled with simvastatin 20 mg:a double-blind, randomized comparative study. Clin Ther, 2011;33(1):1-12.
[121]Arora MK, Reddy K, Balakumar P. The low dose combination of fenofibrate and rosiglitazone halts the progression of diabetes-induced experimental nephropathy. Eur J Pharmacol,2010; 636(1-3):137-144.
[122]Frank C. Brosius III. New insights into the mechanisms of fibrosis and sclerosis in diabetic nephropathy. Rev Endocr Metab Disord,2008; 9(4):245-254.
[123]Pinzani, M. Antifibrotic Drugs, in Portal Hypertension V:Proceedings of the Fifth Baveno International Consensus Workshop, Fifth Edition (ed de Franchis R), Wiley-Blackwell, Oxford, UK,2011,211-217
[124]Richeldi L, Yasothan U, Kirkpatrick P. Pirfenidone. Nat Rev Drug Discov, 2011; 10(7):489-490.
[125]Iyer SN, Wild JS, Schiedt MJ, et al. Dietary intake of pirfenidone ameliorates bleomycin-induced lung fibrosis in hamsters. J Lab Clin Med,1995; 125(6):779-785.
[126]Hewitson TD, Kelynack KJ, Tait MG, et al. Pirfenidone reduces in vitro rat renal fibroblast activation and mitogenesis. J Nephrol,2001; 14(6):453-460.
[127]Shimizu T, Kuroda T, Hata S, et al. Pirfenidone improves renal function and fibrosis in the post-obstructed kidney. Kidney Int,1998; 54(1):99-109.
[128]Leh S, Vaagnes O, Margolin SB, et al. Pirfenidone and candesartan ameliorate morphological damage in mild chronic anti-GBM nephritis in rats. Nephrol Dial Transplant,2005; 20(1):71-82.
[129]Miric G, Dallemagne C, Endre Z, et al. Reversal of cardiac and renal fibrosis by pirfenidone and spironolactone in streptozotocin-diabetic rats. Br J Pharmacol,2001; 133(5):687-694.
[130]Ramachandra Rao SP, Zhu Y, Ravasi T, et al. Pirfenidone is renoprotective in diabetic kidney disease. J Am Soc Nephrol,2009; 20(8):1765-1775.
[131]Cho ME, Smith DC, Branton MH, et al. Pirfenidone slows renal function decline in patients with focal segmental glomerulosclerosis. Clin J Am Soc Nephrol,2007; 2(5):906-913.
[132]Lao LJ, Hu GY, Shi YE. Composition and method for treating fibrotic diseases: US 2009/0258911 A1[P].2009-10-15
[133]Yuan Q, Wang R, Peng Y, et al. Fluorofenidone attenuates tubulointerstitial fibrosis by inhibiting TGF-β(1)-induced fibroblast activation. Am J Nephrol, 2011; 34(2):181-94.
[134]Li BX, Tang YT, Wang W, et al. Fluorofenidone attenuates renal interstitial fibrosis in the rat model of obstructive nephropathy. Mol Cell Biochem.2011; 354(1-2):263-273.
[135]Tao LJ, Zhang J, Hu GY. Effects of 1-(3-fluorophenyl)-5-methyl-2-(1H)-pyridone on renal fibroblast in rats. Zhong Nan Da Xue Xue Bao Yi Xue Ban, 2004;29(2):139-141.
[136]Wang L, Hu GY, Shen H, et al. Fluorofenidone inhibits TGF-betal induced CTGF via MAPK pathways in mouse mesangial cells. Pharmazie,2009; 64(10):680-684.
[137]Peng ZZ, Hu GY, Shen H, et al. Fluorofenidone attenuates collagen I and transforming growth factor-beta1 expression through a nicotinamide adenine dinucleotide phosphate oxidase-dependent way in NRK-52E cells. Nephrology (Carlton),2009; 14(6):565-572.
[138]Wang LH, Liu JS, Ning WB, et al. Fluorofenidone attenuates diabetic nephropathy and kidney fibrosis in db/db mice. Pharmacology,2011; 88(1-2):88-99.
[139]Sugaru E, Sakai M, Horigome K, et al. SMP-534 inhibits TGF-beta-induced ECM production in fibroblast cells and reduces mesangial matrix accumulation in experimental glomerulonephritis. Am J Physiol Renal Physiol,2005; 289(5):F998-1004.
[140]Sugaru E, Nakagawa T, Ono-Kishino M, et al. SMP-534 ameliorates progression of glomerular fibrosis and urinary albumin in diabetic db/db mice. Am J Physiol Renal Physiol.2006; 290(4):F813-820.
[141]Sugaru E, Nakagawa T, Ono-Kishino M, et al. Amelioration of established diabetic nephropathy by combined treatment with SMP-534 (antifibrotic agent) and losartan in db/db mice. Nephron Exp Nephrol,2007; 105(2):e45-52.
[142]Hirano T, Kashiwazaki K, Moritomo Y, et al. Albuminuria is directly associated with increased plasma PAI-1 and factor VII levels in NIDDM patients. Diabetes Res Clin Pract.1997; 36(1):11-18.
[143]Seo JY, Park J, Yu MR, et al. Positive feedback loop between plasminogen activator inhibitor-1 and transforming growth factor-betal during renal fibrosis in diabetes. Am J Nephrol,2009; 30(6):481-490.
[144]Rerolle JP, Hertig A, Nguyen G, et al. Plasminogen activator inhibitor type 1 is a potential target in renal fibrogenesis. Kidney Int,2000; 58(5):1841-1850.
[145]Izuhara Y, Takahashi S, Nangaku M, et al. Inhibition of plasminogen activator inhibitor-1:its mechanism and effectiveness on anticoagulation and anti-fibrosis. Arterioscler Thromb Vasc Biol,2008; 28(4):672-677.
[146]Huang Y, Border WA, Yu L, et al. A PAI-1 mutant, PAI-1R, slows progression of diabetic nephropathy. J Am Soc Nephrol,2008; 19(2):329-338.
[147]Cheng H, Fan X, Moeckel GW, et al. Podocyte COX-2 exacerbates diabetic nephropathy by increasing podocyte (pro)rennin receptor expression. J Am Soc Nephrol,2011; 22(7):1240-1251.
[148]Zhou QL, Peng WS, Yuichiro Y, et al. Effect of losartan on cyclooxygenase-2 expression in normal human mesangial cells and kidneys of rats with diabetic nephropathy. Zhong Nan Da Xue Xue Bao Yi Xue Ban,2008; 33(9):790-799.
[149]Ko GJ, Kang YS, Han SY, et al. Pioglitazone attenuates diabetic nephropathy through an anti-inflammatory mechanism in type 2 diabetic rats. Nephrol Dial Transplant.2008; 23(9):2750-2760.
[150]Radfar M, Larijani B, Hadjibabaie M, et al. Effects of pentoxifylline on oxidative stress and levels of EGF and NO in blood of diabetic type-2 patients; a randomized, double-blind placebo-controlled clinical trial. Biomed Pharmacother,2005; 59(6):302-306.
[151]Sinzinger H. Pentoxifylline enhances formation of prostacyclin from rat vascular and renal tissue. Prostaglandins Leukot Med,1983; 12(2):217-226.
[152]Han KH, Han SY, Kim HS, et al. Prolonged administration enhances the renoprotective effect of pentoxifylline via anti-inflammatory activity in streptozotocin-induced diabetic nephropathy. Inflammation,2010; 33(3):137-143.
[153]Chen YM, Lin SL, Chiang WC, et al. Pentoxifylline ameliorates proteinuria through suppression of renal monocyte chemoattractant protein-1 in patients with proteinuric primary glomerular diseases. Kidney Int,2006; 69(8):1410-1415.
[154]Badri S, Dashti-Khavidaki S, Lessan-Pezeshki M, et al. A review of the potential benefits of pentoxifylline in diabetic and non-diabetic proteinuria. J Pharm Pharm Sci,2011; 14(1):128-137.
[155]McCormick BB, Sydor A, Akbari A, et al. The effect of pentoxifylline on proteinuria in diabetic kidney disease:a meta-analysis. Am J Kidney Dis,2008; 52(3):454-463.
[156]Navarro-Gonzalez JF, Muros M, Mora-Fernandez C, et al. Pentoxifylline for Renoprotection in Diabetic Nephropathy:the PREDIAN study. Rationale and basal results. J Diabetes Complications,2011; 25(5):314-319.
[157]Chakraborti AK, Garg SK, Kumar R, et al. Progress in COX-2 inhibitors:a journey so far. Curr Med Chem,2010; 17(15):1563-1593.
[158]Hao CM, Breyer MD. Physiologic and pathophysiologic roles of lipid mediators in the kidney. Kidney Int,2007; 71(11):1105-1115.
[159]Yabuki A, Taniguchi K, Yamato O. Immunohistochemical examination of cyclooxygenase-2 and renin in a KK-A(y) mouse model of diabetic nephropathy. Exp Anim,2010; 59(4):479-486.
[160]Quilley J, Santos M, Pedraza P. Renal protective effect of chronic inhibition of COX-2 with SC-58236 in streptozotocin-diabetic rats. Am J Physiol Heart Circ Physiol,2011; 300(6):H2316-2322.
[161]Cheng HF, Wang CJ, Moeckel GW, et al. Cyclooxygenase-2 inhibitor blocks expression of mediators of renal injury in a model of diabetes and hypertension. Kidney Int,2002; 62(3):929-939.
[162]Komers R, Lindsley JN, Oyama TT, et al. Cyclo-oxygenase-2 inhibition attenuates the progression of nephropathy in uninephrectomized diabetic rats. Clin Exp Pharmacol Physiol,2007; 34(1-2):36-41.
[163]Sinsakul M, Sika M, Rodby R, et al. A randomized trial of a 6-week course of celecoxib on proteinuria in diabetic kidney disease. Am J Kidney Dis,2007; 50(6):946-951.
[164]Cherney DZ, Miller JA, Scholey JW, et al. The effect of cyclooxygenase-2 inhibition on renal hemodynamic function in humans with type 1 diabetes. Diabetes,2008; 57(3):688-695.
[165]Giacco F, Brownlee M. Oxidative stress and diabetic complications. Circ Res, 2010; 107(9):1058-1070.
[166]Ceriello A, Morocutti A, Mercuri F, et al. Defective intracellular antioxidant enzyme production in type 1 diabetic patients with nephropathy. Diabetes,2000; 49(12):2170-2177.
[167]Farvid MS, Jalali M, Siassi F, et al. Comparison of the effects of vitamins and/or mineral supplementation on glomerular and tubular dysfunction in type 2 diabetes. Diabetes Care,2005; 28(10):2458-2464.
[168]Gaede P, Poulsen HE, Parving HH, et al. Double-blind, randomized study of the effect of combined treatment with vitamin C and E on albuminuria in Type 2 diabetic patients. Diabet Med,2001;18(9):756-760.
[169]Mann JF, Lonn EM, Yi Q, et al. Effects of vitamin E on cardiovascular outcomes in people with mild-to-moderate renal insufficiency:results of the HOPE study. Kidney Int,2004; 65(4):1375-1380.
[170]Endo K, Miyashita Y, Sasaki H, et al. Probucol delays progression of diabetic nephropathy. Diabetes Res Clin Pract,2006; 71(2):156-163.
[171]Goicoechea M, de Vinuesa SG, Verdalles U, et al. Effect of allopurinol in chronic kidney disease progression and cardiovascular risk. Clin J Am Soc Nephrol,2010; 5(8):1388-1393.
[172]Morcos M, Borcea V, Isermann B, et al. Effect of alpha-lipoic acid on the progression of endothelial cell damage and albuminuria in patients with diabetes mellitus:an exploratory study. Diabetes Res Clin Pract,2001; 52(3):175-183.
[173]Zibadi S, Rohdewald PJ, Park D, et al. Reduction of cardiovascular risk factors in subjects with type 2 diabetes by Pycnogenol supplementation. Nutr Res, 2008; 28(5):315-320.
[174]Kadhim HM, Ismail SH, Hussein KI, et al. Effects of melatonin and zinc on lipid profile and renal function in type 2 diabetic patients poorly controlled with metformin, J Pineal Res 2006; 41(2):189-193.
[175]Kim HJ, Vaziri ND. Contribution of impaired Nrf2-Keapl pathway to oxidative stress and inflammation in chronic renal failure. Am J Physiol Renal Physiol,2010; 298(3):F662-F671.
[176]Pergola PE, Raskin P, Toto RD, et al. Bardoxolone methyl and kidney function in CKD with type 2 diabetes. N Engl J Med,2011; 365(4):327-336.
[177]Tojo A, Asaba K, Onozato ML. Suppressing renal NADPH oxidase to treat diabetic nephropathy. Expert Opin Ther Targets,2007; 11(8):1011-1018.
[178]Thallas-Bonke V, Coughlan MT, Bach LA, et al. Preservation of kidney function with combined inhibition of NADPH oxidase and angiotensin-converting enzyme in diabetic nephropathy. Am J Nephrol 2010; 32(1):73-82.
[179]Asaba K, Tojo A, Onozato ML, et al. Effects of NADPH oxidase inhibitor in diabetic nephropathy. Kidney Int,2005; 67(5):1890-1898.
[180]Shi XY, Hou FF, Niu HX, et al. Advanced oxidation protein products promote inflammation in diabetic kidney through activation of renal nicotinamide adenine dinucleotide phosphate oxidase. Endocrinology 2008; 149(4):1829-1839.
[181]Ahmad A, Mondello S, Di Paola R, et al. Protective effect of apocynin, a NADPH-oxidase inhibitor, against contrast-induced nephropathy in the diabetic rats:A comparison with n-acetylcysteine. Eur J Pharmacol,2012; 674(2-3):397-406.
[182]DeRubertis FR, Craven PA, Melhem MF. Acceleration of diabetic renal injury in the superoxide dismutase knockout mouse:effects of tempol. Metabolism. 2007; 56(9):1256-1264.
[183]Fujita H, Fujishima H, Chida S, et al. Reduction of renal superoxide dismutase in progressive diabetic nephropathy. J Am Soc Nephrol,2009; 20(6):1303-1313.
[184]Peixoto EB, Pessoa BS, Biswas SK, et al. Antioxidant SOD mimetic prevents NADPH oxidase-induced oxidative stress and renal damage in the early stage of experimental diabetes and hypertension. Am J Nephrol,2009; 29(4):309-318.
[185]Rodriguez F, Lopez B, Perez C, et al. Chronic tempol treatment attenuates the renal hemodynamic effects induced by a heme oxygenase inhibitor in streptozotocin diabetic rats. Am J Physiol Regul Integr Comp Physiol 2011; 301(5):R1540-1548.
[186]Nassar T, Kadery B, Lotan C, et al. Effects of the superoxide dismutase-mimetic compound tempol on endothelial dysfunction in streptozotocin-induced diabetic rats. Eur J Pharmacol,2002; 436(1-2):111-118.
[187]Asaba K, Tojo A, Onozato ML, et al. Double-edged action of SOD mimetic in diabetic nephropathy. J Cardiovasc Pharmacol 2007; 49(1):13-19.
[188]Juhasz B, Varga B, Gesztelyi R, et al. Resveratrol:a multifunctional cytoprotective molecule. Curr Pharm Biotechnol,2010; 11(8):810-818.
[189]Sharma S, Anjaneyulu M, Kulkarni SK, et al 1. Resveratrol, a polyphenolic phyto-alexin, attenuates diabetic nephropathy in rats. Pharmacology,2006; 76(2):69-75.
[190]Kitada M, Kume S, Imaizumi N, et al. Resveratrol improves oxidative stress and protects against diabetic nephropathy through normalization of Mn-SOD dysfunction in AMPK/SIRT1-independent pathway. Diabetes,2011; 60(2):634-643.
[191]Chang CC, Chang CY, Wu YT, et al. Resveratrol retards progression of diabetic nephropathy through modulations of oxidative stress, proinflammatory cytokines, and AMP-activated protein kinase. J Biomed Sci.2011; 18(1):47-57.
[192]Ding DF, You N, Wu XM, et al. Resveratrol attenuates renal hypertrophy in early-stage diabetes by activating AMPK. Am J Nephrol,2010; 31(4):363-374.
[193]Tikoo K, Singh K, Kabra D, et al. Change in histone H3 phosphorylation, MAP kinase p38, SIR 2 and p53 expression by resveratrol in preventing streptozotocin induced type I diabetic nephropathy. Free Radic Res,2008; 42(4):397-404.
[194]Singh R, Barden A, Mori T, Beilin L. Advanced glycation end-products:a review. Diabetologia,2001; 44(2):129-146.
[195]Reiniger N, Lau K, McCalla D, et al. Deletion of the receptor for advanced glycation end products reduces glomerulosclerosis and preserves renal function in the diabetic OVE26 mouse. Diabetes,2010; 59(8):2043-2054.
[196]Forbes JM, Cooper ME, Oldfield MD, Thomas MC.2003. Role of advanced glycation end products in diabetic nephropathy. J Am Soc Nephrol, 14:S254-258
[197]Yamagishi S, Matsui T. Advanced glycation end products, oxidative stress and diabetic nephropathy. Oxid Med Cell Longev,2010; 3(2):101-108.
[198]Abdel-Rahman E, Bolton WK. Pimagedine:a novel therapy for diabetic nephropathy. Expert Opin Investig, Drugs,2002;11(4):565-574.
[199]Bolton WK, Cattran DC, Williams ME, et al. Randomized trial of an inhibitor of formation of advanced glycation end products in diabetic nephropathy. Am J Nephrol,2004;24(1):32-40.
[200]Suji G, Sivakami S. DNA damage by free radical production by aminoguanidine. Ann N Y Acad Sci,2006; 1067:191-199.
[201]Chetyrkin SV, Zhang W, Hudson BG, et al. Pyridoxamine protects proteins from functional damage by 3-deoxyglucosone:mechanism of action of pyridoxamine. Biochemistry,2008; 47(3):997-1006.
[202]Alderson NL, Chachich ME, Youssef NN, et al. The AGE inhibitor pyridoxamine inhibits lipemia and development of renal and vascular disease in Zucker obese rats. Kidney Int,2003; 63(6):2123-2133.
[203]Tanimoto M, Gohda T, Kaneko S, et al. Effect of pyridoxamine (K-163), an inhibitor of advanced glycation end products, on type 2 diabetic nephropathy in KK-A(y)/Ta mice. Metabolism,2007; 56(2):160-167.
[204]Williams ME, Bolton WK, Khalifah RG, et al. Effects of pyridoxamine in combined phase 2 studies of patients with type 1 and type 2 diabetes and overt nephropathy. Am J Nephrol,2007; 27(6):605-614.
[205]Pacal L, Tomandl J, Svojanovsky J, et al. Role of thiamine status and genetic variability in transketolase and other pentose phosphate cycle enzymes in the progression of diabetic nephropathy. Nephrol Dial Transplant,2011; 26(4):1229-1236.
[206]Babaei-Jadidi R, Karachalias N, Kupich C, et al. High dose thiamine therapy counters dyslipidaemia in streptozotocin-induced diabetic rats. Diabetologia, 2004;47(12):2235-2246.
[207]Rabbani N, Alam SS, Riaz S, et al. High-dose thiamine therapy for patients with type 2 diabetes and microalbuminuria:a randomised, double-blind placebo-controlled pilot study. Diabetologia,2009; 52(2):208-212.
[208]Riaz S, Skinner V, Srai SK. Effect of high dose thiamine on the levels of urinary protein biomarkers in diabetes mellitus type 2. J Pharm Biomed Anal, 2011; 54(4):817-825.
[209]Balakumar P, Rohilla A, Krishan P, et al. The multifaceted therapeutic potential of benfotiamine. Pharmacol Res,2010; 61(6):482-488.
[210]Babaei-Jadidi R, Karachalias N, Ahmed N, et al. Prevention of incipient diabetic nephropathy by high-dose thiamine and benfotiamine. Diabetes,2003; 52(8):2110-2120.
[211]Alkhalaf A, Klooster A, van Oeveren W, et al. A double-blind, randomized, placebo-controlled clinical trial on benfotiamine treatment in patients with diabetic nephropathy. Diabetes Care,2010; 33(1):1598-1601.
[212]Wilkinson-Berka JL, Kelly DJ, Koerner SM, et al. ALT-946 and aminoguanidine, inhibitors of advanced glycation, improve severe nephropathy in the diabetic transgenic (mREN-2)27 rat. Diabetes,2002; 51(11):3283-3289.
[213]Goh SY, Jasik M, Cooper ME. Agents in development for the treatment of diabetic nephropathy. Expert Opin Emerg Drugs,2008; 13(3):447-463.
[214]Vasan S, Zhang X, Zhang X, et al. An agent cleaving glucose-derived protein crosslinks in vitro and in vivo. Nature,1996; 382(6588):275-278.
[215]Peppa M, Brem H, Cai W, et al. Prevention and reversal of diabetic nephropathy in db/db mice treated with alagebrium (ALT-711). Am J Nephrol, 2006; 26(5):430-436.
[216]Coughlan MT, Forbes JM, Cooper ME. Role of the AGE crosslink breaker, alagebrium, as a renoprotective agent in diabetes. Kidney Int Suppl,2007; 106:S54-60.
[217]Kass DA, Shapiro EP, Kawaguchi M, et al. Improved arterial compliance by a novel advanced glycation endproduct crosslink breaker. Circulation,2001; 104(13):1464-1470.
[218]Zieman SJ, Melenovsky V, Clattenburg L, et al. Advanced glycation endproduct crosslink breaker (alagebrium) improves endothelial function in patients with isolated systolic hypertension. J Hypertens,2007; 25(3):577-583.
[219]Hartog JW, Willemsen S, van Veldhuisen DJ, et al. Effects of alagebrium, an advanced glycation endproduct breaker, on exercise tolerance and cardiac function in patients with chronic heart failure. Eur J Heart Fail,2011; 13(8):899-908.
[220]Joshi D, Gupta R, Dubey A, et al. TRC4186, a novel AGE-breaker, improves diabetic cardiomyopathy and nephropathy in ob-ZSF1 model of type 2 diabetes. J Cardiovasc Pharmacol,2009; 54(1):72-81.
[221]Chandra KP, Shiwalkar A, Kotecha J, et al. Phase I clinical studies of the advanced glycation end-product (AGE)-breaker TRC4186:safety, tolerability and pharmacokinetics in healthy subjects. Clin Drug Investig\,2009; 29(9):559-575.
[222]Schmidt AM, Hori O, Cao R, et al. RAGE:a novel cellular receptor for advanced glycation end products. Diabetes,1996; 45(suppl 3):S77-80.
[223]Penfold SA, Coughlan MT, Patel SK, et al. Circulating high-molecular-weight RAGE ligands activate pathways implicated in the development of diabetic nephropathy. Kidney Int,2010; 78(3):287-95.
[224]Katakami N, Matsuhisa M, Kaneto H, et al. Decreased endogenous secretory advanced glycation end product receptor in type 1 diabetic patients:its possible association with diabetic vascular complications. Diabetes Care,2005; 28(11):2716-2821.
[225]Jensen LJ, Denner L, Schrijvers BF, et al. Renal effects of a neutralising RAGE antibody in long-term streptozotocin-diabetic mice. J Endocrinol,2006; 188(3):493-501.
[226]Maeda S, Matsui T, Takeuchi M, et al. Pigment epithelium-derived factor (PEDF) inhibits proximal tubular cell injury in early diabetic nephropathy by suppressing advanced glycation end products (AGEs)-receptor (RAGE) axis. Pharmacol Res,2011; 63(3):241-248.
[227]Sourris KC, Forbes JM. Interactions between advanced glycation end-products (AGE) and their receptors in the development and progression of diabetic nephropathy-are these receptors valid therapeutic targets. Curr Drug Targets 2009; 10(1):42-50.
[228]Sharma K, Jin Y, Guo J, et al. Neutralization of TGF-beta by anti-TGF-beta antibody attenuates kidney hypertrophy and the enhanced extracellular matrix gene expression in STZ-induced diabetic mice. Diabetes,1996; 45(4):522-530.
[229]Ziyadeh FN, Hoffman BB, Han DC, et al. Long-term prevention of renal insufficiency, excess matrix gene expression, and glomerular mesangial matrix expansion by treatment with monoclonal antitransforming growth factor-beta antibody in db/db diabetic mice. Proc Natl Acad Sci U S A.2000; 97(14):8015-8020.
[230]Benigni A, Zoja C, Campana M, et al. Beneficial effect of TGFbeta antagonism in treating diabetic nephropathy depends on when treatment is started. Nephron Exp Nephrol,2006; 104(4):e158-68.
[231]Hill C, Flyvbjerg A, Rasch R, et al. Transforming growth factor-beta2 antibody attenuates fibrosis in the experimental diabetic rat kidney. J Endocrinol, 2001;170(3):647-651.
[232]Flyvbjerg A, Khatir D, Jensen LJN, et al. Long-term renal effects of a neutralizing CTGF-antibody in obese type 2 diabetic mice [Abstract]. J Am Soc Nephrol,2004; 15:261 A.
[233]Adler SG, Schwartz S, Williams ME, et al. Phase 1 study of anti-CTGF monoclonal antibody in patients with diabetes and microalbuminuria. Clin J Am Soc Nephrol,2010; 5(8):1420-1428.
[234]de Vriese AS, Tilton RG, Elger M, et al. Antibodies against vascular endothelial growth factor improve early renal dysfunction in experimental diabetes. J Am Soc Nephrol,2001; 12(5):993-1000.
[235]Flyvbjerg A, Dagnaes-Hansen F, De Vriese AS, et al. Amelioration of long-term renal changes in obese type 2 diabetic mice by a neutralizing vascular endothelial growth factor antibody. Diabetes,2002; 51(10):3090-3094.
[236]Schrijvers BF, Flyvbjerg A, Tilton RG, et al. A neutralizing VEGF antibody prevents glomerular hypertrophy in a model of obese type 2 diabetes, the Zucker diabetic fatty rat. Nephrol Dial Transplant,2006; 21(2):324-329.
[237]Schrijvers BF, De Vriese AS, Tilton RG, et al. Inhibition of vascular endothelial growth factor (VEGF) does not affect early renal changes in a rat model of lean type 2 diabetes. Horm Metab Res,2005; 37(1):21-25.
[238]Boor P, Floege J. Chronic kidney disease growth factors in renal fibrosis. Clin Exp Pharmacol Physiol,2011; 38(7):391-400.
[239]Hui L, Hong Y, Jingjing Z, et al. HGF suppresses high glucose-mediated oxidative stress in mesangial cells by activation of PKG and inhibition of PKA. Free Radic Biol Med,2010; 49(3):467-73.
[240]Mizuno S, Nakamura T. Suppressions of chronic glomerular injuries and TGF-beta 1 production by HGF in attenuation of murine diabetic nephropathy. Am J Physiol Renal Physiol,2004; 286(1):F134-143.
[241]Mou S, Wang Q, Shi B, et al. Hepatocyte growth factor ameliorates progression of interstitial injuries in tubular epithelial cells. Scand J Urol Nephrol,2010; 44(2):121-128.
[242]Yang J, Liu Y. Blockage of tubular epithelial to myofibroblast transition by hepatocyte growth factor prevents renal interstitial fibrosis. J Am Soc Nephrol, 2002; 13(1):96-107.
[243]Mou S, Wang Q, Shi B, et al. Hepatocyte growth factor suppresses transforming growth factor-beta-1 and type III collagen in human primary renal fibroblasts. Kaohsiung J Med Sci,2009; 25(11):577-587.
[244]Kagawa T, Takemura G, Kosai K, et al. Hepatocyte growth factor gene therapy slows down the progression of diabetic nephropathy in db/db mice. Nephron Physiol,2006; 102(3-4):p92-102.
[245]Dai C, Yang J, Bastacky S, et al. Intravenous administration of hepatocyte growth factor gene ameliorates diabetic nephropathy in mice. J Am Soc Nephrol,2004; 15(10):2637-2647.
[246]Cruzado JM, Lloberas N, Torras J, et al. Regression of advanced diabetic nephropathy by hepatocyte growth factor gene therapy in rats. Diabetes,2004; 53(4):1119-1127.
[247]Zeisberg M, Hanai J, Sugimoto H, et al. BMP-7 counteracts TGF-betal-induced epithelial-to-mesenchymal transition and reverses chronic renal injury. Nat Med,2003; 9(7):964-968.
[248]Zeisberg M, Shah AA, Kalluri R. Bone morphogenic protein-7 induces mesenchymal to epithelial transition in adult renal fibroblasts and facilitates regeneration of injured kidney. J Biol Chem,2005; 280(9):8094-8100.
[249]Xu Y, Wan J, Jiang D, et al. BMP-7 counteracts TGF-betal-induced epithelial-to-mesenchymal transition in human renal proximal tubular epithelial cells. J Nephrol,2009; 22(3):403-410.
[250]Dudas PL, Argentieri RL, Farrell FX. BMP-7 fails to attenuate TGF-betal-induced epithelial-to-mesenchymal transition in human proximal tubule epithelial cells. Nephrol Dial Transplant,2009; 24(5):1406-1416.
[251]Wang S, Hirschberg R. BMP7 antagonizes TGF-beta-dependent fibrogenesis in mesangial cells. Am J Physiol Renal Physiol,2003; 284(5):F1006-1013.
[252]Sugimoto H, Grahovac G, Zeisberg M, et al. Renal fibrosis and glomerulosclerosis in a new mouse model of diabetic nephropathy and its regression by bone morphogenic protein-7 and advanced glycation end product inhibitors. Diabetes 2007; 56(7):1825-1833.
[253]Wang S, Chen Q, Simon TC, et al. Bone morphogenic protein-7 (BMP-7), a novel therapy for diabetic nephropathy. Kidney Int,2003; 63(6):2037-2049.
[254]Wang S, de Caestecker M, Kopp J, et al. Renal bone morphogenetic protein-7 protects against diabetic nephropathy. J Am Soc Nephrol,2006; 17(9):2504-2512.
[255]Noh H, King GL. The role of PKC activation in diabetic nephropathy. Kidney Int Suppl,2007; 106:S49-53
[256]Parker PJ, Murray-Rust J. PKC at a glance. J Cell Sci,2004; 117(Pt 2):131-132.
[257]Li J, Gobe G. PKC activation and its role in kidney disease. Nephrology,2006; 11(5):428-434.
[258]Koya D, Haneda M, Nakagawa H, et al. Amelioration of accelerated diabetic mesangial expansion by treatment with a PKC beta inhibitor in diabetic db/db mice, a rodent model for type 2 diabetes. FASEB J,2000; 14(3):439-447.
[259]Kelly DJ, Zhang Y, Hepper C, et al. Protein kinase C beta inhibition attenuates the progression of experimental diabetic nephropathy in the presence of continued hypertension. Diabetes,2003; 52(2):512-518.
[260]Tuttle KR, Bakris GL, Toto RD, et al. The effect of ruboxistaurin on nephropathy in type 2 diabetes. Diabetes Care.2005; 28(11):2686-2690.
[261]Thallas-Bonke V, Lindschau C, Rizkalla B, et al. Attenuation of extracellular matrix accumulation in diabetic nephropathy by the advanced glycation end product cross-link breaker ALT-711 via a protein kinase C-alpha-dependent pathway. Diabetes,2004; 53(11):2921-2930.
[262]Thallas-Bonke V, Thorpe SR, Coughlan MT, et al. Inhibition of NADPH oxidase prevents advanced glycation end product-mediated damage in diabetic nephropathy through a protein kinase C-a-dependent pathway. Diabetes,2008; 57(2):460-469.
[263]Godel M, Hartleben B, Herbach N, et al. Role of mTOR in podocyte function and diabetic nephropathy in humans and mice. J Clin Invest,2011; 121(6):2197-2209.
[264]Yang Y, Wang J, Qin L, et al. Rapamycin prevents early steps of the development of diabetic nephropathy in rats. Am J Nephrol,2007; 27(5):495-502.
[265]Wittmann S, Daniel C, Stief A, et al. Long-term treatment of sirolimus but not cyclosporine ameliorates diabetic nephropathy in rats. Transplantation,2009; 87(9):1290-1299.
[266]Sakaguchi M, Isono M, Isshiki K, et al. Inhibition of mTOR signaling with rapamycin attenuates renal hypertrophy in the early diabetic mice. Biochem Biophys Res Commun,2006; 340(1):296-301.
[267]Mori H, Inoki K, Masutani K, et al. The mTOR pathway is highly activated in diabetic nephropathy and rapamycin has a strong therapeutic potential. Biochem Biophys Res Commun,2009; 384(4):471-475.
[268]Cheng L, Chen J, Mao X. Everolimus vs. rapamycin for treating diabetic nephropathy in diabetic mouse model. J Huazhong Univ Sci Technolog Med Sci,2011;31(4):457-462.
[269]Navarro-Gonzalez JF, Mora-Fernandez C, et al. Inflammatory molecules and pathways in the pathogenesis of diabetic nephropathy. Nat Rev Nephrol,2011; 7(6):327-340.
[270]Tamada S, Nakatani T, Asai T, et al. Inhibition of nuclear factor-kappaB activation by pyrrolidine dithiocarbamate prevents chronic FK506 nephropathy. Kidney Int,2003; 63(1):306-314.
[271]Fujihara CK, Antunes GR, Mattar AL, et al. Chronic inhibition of nuclear factor-kappaB attenuates renal injury in the 5/6 renal ablation model. Am J Physiol Renal Physiol,2007; 292(1):F92-99.
[272]Tapia E, Sanchez-Gonzalez DJ, Medina-Campos ON, et al. Treatment with pyrrolidine dithiocarbamate improves proteinuria, oxidative stress, and glomerular hypertension in overload proteinuria. Am J Physiol Renal Physiol, 2008;295(5):F1431-1439.
[273]Malaguarnera L, Pilastro MR, DiMarco R, et al. Cell death in human acute myelogenous leukemic cells induced by pyrrolidinedithiocarbamate. Apoptosis, 2003; 8(5):539-545.
[274]Morais C, Gobe G, Johnson DW, et al. Anti-angiogenic actions of pyrrolidine dithiocarbamate, a nuclear factor kappa B inhibitor. Angiogenesis,2009; 12(4):365-379.
[275]Deb DK, Chen Y, Zhang Z, et al.1,25-Dihydroxyvitamin D3 suppresses high glucose-induced angiotensinogen expression in kidney cells by blocking the NF-{kappa}B pathway. Am J Physiol Renal Physiol.2009; 296(5):F1212-218.
[276]Liu W, Zhang X, Liu P, et al. Effects of berberine on matrix accumulation and NF-kappa B signal pathway in alloxan-induced diabetic mice with renal injury. Eur J Pharmacol,2010; 638(1-3):150-155.
[277]Seaquist ER, Goetz FC, Rich S, et al. Familial clustering of diabetic kidney disease. Evidence for genetic susceptibility to diabetic nephropathy. N Engl J Med,1989; 320(18):1161-1165.
[278]Conway BR, Maxwell AP. Genetics of diabetic nephropathy:are there clues to the understanding of common kidney diseases? Nephron Clin Pract,2009; 112(4):c213-221.
[279]Susztak K, Sharma K, Schiffer M, et al. Genomic strategies for diabetic nephropathy. J Am Soc Nephrol,2003; 14(8 Suppl 3):S271-278.
[280]Smith MP, Banks RE, Wood SL, et al. Application of proteomic analysis to the study of renal diseases. Nat Rev Nephrol,2009; 5(12):701-712.
[2]Ning G, Hong J, Bi Y, et al. Progress in diabetes research in China. J Diabetes,2009; 1:163-172.
[3]Rossing P, de Zeeuw D. Need for better diabetes treatment for improved renal outcome. Kidney Int Suppl,2011; 120:S28-32.
[4]Fioretto P, Mauer M. Histopathology of diabetic nephropathy. Semin Nephrol,2007; 27(2):195-207.
[5]Kamenetsky I, Rangayyan RM, Benediktsson H. Analysis of the glomerular basement membrane in images of renal biopsies using the split-and-merge method:a pilot study. J Digit Imaging,2010; 23(4):463-474.
[6]Ayodele OE, Alebiosu CO, Salako BL. Diabetic nephropathy-a review of the natural history, burden, risk factors and treatment. J Natl Med Assoc, 2004; 96(11):1445-1454.
[7]Blazquez-Medela AM, Lopez-Novoa JM, Martinez-Salgado C. Mechanisms involved in the genesis of diabetic nephropathy. Curr Diabetes Rev,2010; 6(2):68-87.
[8]Kashihara N, Haruna Y, Kondeti VK, et al. Oxidative stress in diabetic nephropathy. Curr Med Chem.2010;17(34):4256-4269.
[9]Daroux M, Prevost G, Maillard-Lefebvre H, et al. Advanced glycation end-products:implications for diabetic and non-diabetic nephropathies. Diabetes Metab,2010; 36(1):1-10.
[10]Min D, Lyons JG, Bonner J, et al. Mesangial cell-derived factors alter monocyte activation and function through inflammatory pathways: possible pathogenic role in diabetic nephropathy. Am J Physiol Renal Physiol,2009; 297(5):F 1229-237.
[11]Chawla T, Sharma D, Singh A. Role of the renin angiotensin system in diabetic nephropathy. World J Diabetes,2010; 1(5):141-145.
[12]Gnudi L, Thomas SM, Viberti G. Mechanical forces in diabetic kidney disease:a trigger for impaired glucose metabolism. J Am Soc Nephrol, 2007; 18:2226-2232.
[13]Ban CR, Twigg SM. Fibrosis in diabetes complications:pathogenic mechanisms and circulating and urinary markers. Vasc Health Risk Manag, 2008; 4(3):575-596.
[14]Thrailkill KM, Clay Bunn R, Fowlkes JL. Matrix metalloproteinases:their potential role in the pathogenesis of diabetic nephropathy. Endocrine, 2009; 35(1):1-10.
[15]Skill NJ, Griffin M, El Nahas AM, et al. Increases in renal epsilon-(gamma-glutamyl)-lysine crosslinks result from compartment-specific changes in tissue transglutaminase in early experimental diabetic nephropathy:pathologic implications. Lab Invest, 2001; 81(5):705-716.
[16]Choudhury D, Tuncel M, Levi M. Diabetic nephropathy-a multifaceted target of new therapies. Discov Med,2010; 10(54):406-415.
[17]Thomas MC, Groop PH. New approaches to the treatment of nephropathy in diabetes. Expert Opin Investig Drugs,2011; 20(8):1057-1071.
[18]Petersen M, Thorikay M, Deckers M, et al. Oral administration of GW788388, an inhibitor of TGF-beta type I and II receptor kinases, decreases renal fibrosis. Kidney Int,2008; 73:705-715.
[19]Li J, Kang SW, Kim JL, et al. Isoliquiritigenin entails blockade of TGF-beta1-SMAD signaling for retarding high glucose-induced mesangial matrix accumulation. J Agric Food Chem,2010; 58:3205-3212.
[20]Sugaru E, Nakagawa T, Ono-Kishino M, et al. SMP-534 ameliorates progression of glomerular fibrosis and urinary albumin in diabetic db/db mice. Am J Physiol Renal Physiol,2006; 290(4):F813-820.
[21]Hirano T, Kashiwazaki K, Moritomo Y, et al. Albuminuria is directly associated with increased plasma PAI-1 and factor VII levels in NIDDM patients. Diabetes Res Clin Pract,1997; 36(1):11-18.
[22]Richeldi L, Yasothan U, Kirkpatrick P. Pirfenidone. Nat Rev Drug Discov, 2011; 10(7):489-490.
[23]Iyer SN, Wild JS, Schiedt MJ, et al. Dietary intake of pirfenidone ameliorates bleomycin-induced lung fibrosis in hamsters. J Lab Clin Med, 1995; 125(6):779-785.
[24]Ramachandra Rao SP, Zhu Y, Ravasi T, et al. Pirfenidone is renoprotective in diabetic kidney disease. J Am Soc Nephrol,2009; 20(8): 1765-1775.
[25]Miric G, Dallemagne C, Endre Z, et al. Reversal of cardiac and renal fibrosis by pirfenidone and spironolactone in streptozotocin-diabetic rats. Br J Pharmacol,2001; 133(5):687-694.
[26]Shimizu T, Kuroda T, Hata S, et al. Pirfenidone improves renal function and fibrosis in the post-obstructed kidney. Kidney Int,1998; 54(1):99-109.
[27]Cho ME, Smith DC, Branton MH, et al. Pirfenidone slows renal function decline in patients with focal segmental glomerulosclerosis. Clin J Am Soc Nephrol,2007; 2(5):906-913.
[28]Lao LJ, Hu GY, Shi YE. Composition and method for treating fibrotic diseases:US 2009/0258911 A1[P].2009-10-15
[29]Yuan Q, Wang R, Peng Y, et al. Fluorofenidone attenuates tubulointerstitial fibrosis by inhibiting TGF-β(1)-induced fibroblast activation. Am J Nephrol,2011; 34(2):181-194.
[30]Li BX, Tang YT, Wang W, et al. Fluorofenidone attenuates renal interstitial fibrosis in the rat model of obstructive nephropathy. Mol Cell Biochem.2011; 354(1-2):263-273.
[31]Tao LJ, Zhang J, Hu GY. Effects of 1-(3-fluorophenyl)-5-methyl-2-(1H)-pyridone on renal fibroblast in rats. Zhong Nan Da Xue Xue Bao Yi Xue Ban,2004; 29(2):139-141.
[32]Peng ZZ, Hu GY, Shen H, et al. Fluorofenidone attenuates collagen I and transforming growth factor-betal expression through a nicotinamide adenine dinucleotide phosphate oxidase-dependent way in NRK-52E cells. Nephrology (Carlton),2009; 14(6):565-572.
[33]Wang L, Hu GY, Shen H, et al. Fluorofenidone inhibits TGF-betal induced CTGF via MAPK pathways in mouse mesangial cells. Pharmazie, 2009; 64(10):680-684.
[34]Sharma K, McCue P, Dunn SR. Diabetic kidney disease in the db/db mouse. Am J Physiol Renal Physiol,2003; 284(6):F1138-1144.
[35]Cohen MP, Lautenslager GT, Shearman CW. Increased urinary type Ⅳ collagen marks the development of glomerular pathology in diabetic d/db mice. Metabolism,2001; 50(12):1435-1440.
[36]Ziyadeh FN, Hoffman BB, Han DC, et al. Long-term prevention of renal insufficiency, excess matrix gene expression, and glomerular mesangial matrix expansion by treatment with monoclonal antitransforming growth factor-beta antibody in db/db diabetic mice. Proc Natl Acad Sci U S A, 2000; 97(14):8015-8020.
[37]Lim AK, Ma FY, Nikolic-Paterson DJ, et al. Antibody blockade of c-fms suppresses the progression of inflammation and injury in early diabetic nephropathy in obese db/db mice. Diabetologia,2009; 52(8):1669-1679.
[38]Fujii M, Inoguchi T, Sasaki S, et al. Bilirubin and biliverdin protect rodents against diabetic nephropathy by downregulating NAD(P)H oxidase. Kidney Int,2010; 78:905-919.
[39]Moriyama T, Oka K, Ueda H, Imai E. Nilvadipine attenuates mesangial expansion and glomerular hypertrophy in diabetic db/db mice, a model for type 2 diabetes. Clin Exp Nephrol,2004; 8:230-236.
[40]Cohen MP, Lautenslager GT, Hud E, et al. Inhibiting albumin glycation attenuates dysregulation of VEGFR-1 and collagen IV subchain production and the development of renal insufficiency. Am J Physiol Renal Physiol,2007; 292:F789-F795.
[41]Cao W, He L, Liu W, Huang Z, et al. Determination of AKF-PD in whole blood of rat by HPLC-UV. J Chromatogr B Analyt Technol Biomed Life Sci 2006; 833:257-259.
[42]Cohen MP, Sharma K, Jin Y, et al. Prevention of diabetic nephropathy in db/db mice with glycated albumin antagonists. A novel treatment strategy. J Clin Invest,1995; 95(5):2338-2345.
[43]Hong SW, Isono M, Chen S, et al. Increased glomerular and tubular expression of transforming growth factor-beta1, its type II receptor, and activation of the Smad signaling pathway in the db/db mouse. Am J Pathol, 2001;158(5):1653-1663.
[44]Mauer SM, Steffes MW, Ellis EN, et al.Structural-functional relationships in diabetic nephropathy. J Clin Invest 1984; 74(4):1143-1155.
[45]Steffes MW, Osterby R, Chavers B, et al. Mesangial expansion as a central mechanism for loss of kidney function in diabetic patients. Diabetes.1989; 38(9):1077-1081.
[46]Moriya T, Tanaka K, Hosaka T, et al. Renal structure as an indicator for development of albuminuria in normo-and microalbuminuric type 2 diabetic patients. Diabetes Res Clin Pract.2008; 82(3):298-304.
[47]Menini S, Iacobini C, Oddi G, et al. Increased glomerular cell (podocyte) apoptosis in rats with streptozotocin-induced diabetes mellitus:role in the development of diabetic glomerular disease. Diabetologia,2007; 50(12):2591-2599.
[48]Rippe C, Rippe A, Torffvit O, et al. Size and charge selectivity of the glomerular filter in early experimental diabetes in rats. Am J Physiol Renal Physiol,2007; 293(5):F1533-538.
[49]Russo LM, Sandoval RM, Campos SB, et al. Impaired tubular uptake explains albuminuria in early diabetic nephropathy. J Am Soc Nephrol. 2009; 20(3):489-494.
[50]Tojo A, Onozato ML, Ha H, et al. Reduced albumin reabsorption in the proximal tubule of early-stage diabetic rats. Histochem Cell Biol,2001; 116(3):269-276.
[51]Chiarelli F, Verrotti A, Mohn A, et al. The importance of microalbuminuria as an indicator of incipient diabetic nephropathy: therapeutic implications. Ann Med,1997; 29(5):439-445.
[52]Kim MJ, Frankel AH, Donaldson M, et al. Oral cholecalciferol decreases albuminuria and urinary TGF-β1 in patients with type 2 diabetic nephropathy on established renin-angiotensin-aldosterone system inhibition. Kidney Int,2011; 80(8):851-860.
[53]Zhang H, Schin M, Saha J, et al. Podocyte-specific overexpression of GLUT1 surprisingly reduces mesangial matrix expansion in diabetic nephropathy in mice. Am J Physiol Renal Physiol,2010; 299(1):F91-98.
[54]Mason RM, Wahab NA. Extracellular matrix metabolism in diabetic nephropathy. J Am Soc Nephrol,2003; 14(5):1358-1373.
[55]Razzaque MS, Koji T, Taguchi T, et al. In situ localization of type III and type IV collagen-expressing cells in human diabetic nephropathy, J Pathol. 1994; 174(2):131-138.
[56]Suzuki D, Miyazaki M, Jinde K, et al 1. In situ hybridization studies of matrix metalloproteinase-3, tissue inhibitor of metalloproteinase-1 and type IV collagen in diabetic nephropathy. Kidney Int,1997; 52(1):111-119.
[57]Joladarashi D, Salimath PV, Chilkunda ND. Diabetes results in structural alteration of chondroitin sulfate/dermatan sulfate in the rat kidney:effects on the binding to extracellular matrix components. Glycobiology,2011; 21(7):960-972.
[58]Huang L, Haylor JL, Hau Z, et al 1. Transglutaminase inhibition ameliorates experimental diabetic nephropathy. Kidney Int,2009; 76(4):383-394.
[59]Brew K, Dinakarpandian D, Nagase H. Tissue inhibitors of metalloproteinases:evolution, structure and function. Biochim Biophys Acta,2000; 1477:267-283.
[60]Williams JM, Zhang J, North P, et al. Evaluation of metalloprotease inhibitors on hypertension and diabetic nephropathy. Am J Physiol Renal Physiol,2011; 300(4):F983-98.
[61]Ishimura E, Nishizawa Y, Shoji S, et al. Serum type III, IV collagens and TIMP in patients with type II diabetes mellitus. Life Sci,1996; 58(16):1331-1337.
[62]Rysz J, Banach M, Stolarek RA, et al. Serum matrix metalloproteinases MMP-2 and MMP-9 and metalloproteinase tissue inhibitors TIMP-1 and TIMP-2 in diabetic nephropathy. J Nephrol.2007; 20(4):444-452.
[63]Shankland SJ, Ly H, Thai K, et al. Glomerular expression of tissue inhibitor of metalloproteinase (TIMP-1) in normal and diabetic rats. J Am Soc Nephrol,1996; 7(1):97-104.
[64]Cruzado JM, Lloberas N, Torras J, et al. Regression of advanced diabetic nephropathy by hepatocyte growth factor gene therapy in rats. Diabetes, 2004; 53(4):1119-1127.
[65]Ito Y, Goldschmeding R, Kasuga H, et al. Expression patterns of connective tissue growth factor and of TGF-beta isoforms during glomerular injury recapitulate glomerulogenesis. Am J Physiol Renal Physiol,2010; 299(3):545-558.
[66]Yang Q, Xie RJ, Yang T, et al. Transforming growth factor-betal and Smad4 signaling pathway down-regulates renal extracellular matrix degradation in diabetic rats. Chin Med Sci J,2007; 22(4):243-249.
[67]Kondo T, Takemura G, Kosai K, et al. Application of an adenoviral vector encoding soluble transforming growth factor-beta type Ⅱ receptor to the treatment of diabetic nephropathy in mice. Clin Exp Pharmacol Physiol, 2008; 35(11):1288-1293.
[68]De Muro P, Faedda R, Fresu P, et al. Urinary transforming growth factor-beta 1 in various types of nephropathy. Pharmacol Res,2004; 49(3):293-298.
[69]Houlihan CA, Akdeniz A, Tsalamandris C, et al. Urinary transforming growth factor-beta excretion in patients with hypertension, type 2 diabetes, and elevated albumin excretion rate:effects of angiotensin receptor blockade and sodium restriction. Diabetes Care 2002; 25(6):1072-1077.
[70]Kolm-Litty V, Sauer U, Nerlich A, et al. High glucose-induced transforming growth factor betal production is mediated by the hexosamine pathway in porcine glomerular mesangial cells. J Clin Invest, 1998; 101(1):160-169.
[71]Qi W, Chen X, Poronnik P, et al. Transforming growth factor-beta/connective tissue growth factor axis in the kidney. Int J Biochem Cell Biol,2008;40(1):9-13.
[72]Wahab NA, Harper K, Mason RM. Expression of extracellular matrix molecules in human mesangial cells in response to prolonged hyperglycaemia. Biochem J,1996; 316 (Pt 3):985-892.
[73]Nakamura T, Miller D, Ruoslahti E, et al. Production of extracellular matrix by glomerular epithelial cells is regulated by transforming growth factor-beta 1. Kidney Int,1992; 41(5):1213-1221.
[74]Davies M, Thomas GJ, Martin J, et al. The purification and characterization of a glomerular-basement-membrane-degrading neutral proteinase from rat mesangial cells. Biochem J,1988; 251(2):419-425.
[75]Marti HP, Lee L, Kashgarian M, et al. Transforming growth factor-beta 1 stimulates glomerular mesangial cell synthesis of the 72-kd type IV collagenase. Am J Pathol,1994; 144(1):82-94.
[76]Weston BS, Wahab NA, Mason RM. CTGF mediates TGF-beta-induced fibronectin matrix deposition by upregulating active alpha5betal integrin in human mesangial cells. J Am Soc Nephrol,2003; 14(3):601-10.
[77]Hills CE, Squires PE. TGF-betal-induced epithelial-to-mesenchymal transition and therapeutic intervention in diabetic nephropathy. Am J Nephrol,2010; 31(1):68-74.
[78]Sharma K, Jin Y, Guo J, et al. Neutralization of TGF-beta by anti-TGF-beta antibody attenuates kidney hypertrophy and the enhanced extracellular matrix gene expression in STZ-induced diabetic mice. Diabetes,1996; 45(4):522-530.
[79]Meran S, Steadman R. Fibroblasts and myofibroblasts in renal fibrosis. Int J Exp Pathol,2011; 92(3):158-167.
[80]Humphreys BD, Lin SL, Kobayashi A, et al. Fate tracing reveals the pericyte and not epithelial origin of myofibroblasts in kidney fibrosis, Am J Pathol.2010; 176(1):85-97.
[81]Rastaldi MP, Ferrario F, Giardino L, et al. Epithelial-mesenchymal transition of tubular epithelial cells in human renal biopsies. Kidney Int, 2002;62(1):137-146.
[82]Li J, Qu X, Bertram JF. Endothelial-myofibroblast transition contributes to the early development of diabetic renal interstitial fibrosis in streptozotocin-induced diabetic mice. Am J Pathol,2009; 175(4):1380-1388.
[83]Ren X, Guan G, Liu G, et al. Irbesartan ameliorates diabetic nephropathy by reducing the expression of connective tissue growth factor and alpha-smooth-muscle actin in the tubulointerstitium of diabetic rats. Pharmacology,2009; 83(2):80-87.
[84]Ina K, Kitamura H, Tatsukawa S, et al. Significance of a-SMA in myofibroblasts emerging in renal tubulointerstitial fibrosis. Histol Histopathol.2011; 26(7):855-866.
[85]Lee S, Kim W, Moon SO, et al. Renoprotective effect of COMP-angiopoietin-1 in db/db mice with type 2 diabetes. Nephrol Dial Transplant 2007; 22(2):396-408.
[86]Benigni A, Zoja C, Coma D, et al. Add-on anti-TGF-beta antibody to ACE inhibitor arrests progressive diabetic nephropathy in the rat. J Am Soc Nephrol,2003;14(7):1816-24.
[87]Kensuke Asaba, Akihiro Tojo, Maristela Lika Onozato, et al. Effects of NADPH oxidase inhibitor in diabetic nephropathy. Kidney International, 2005;67(5):1890-1898.
[88]Simonson MS. Phenotypic transitions and fibrosis in diabetic nephropathy. Kidney Int,2007; 71(9):846-854.
[89]Chiang CK, Inagi R. Glomerular diseases:genetic causes and future therapeutics. Nat Rev Nephrol,2010;6(9):539-554.
[90]Ru Y, Song HM. Progress in the research on the role of mesangial remodeling in glomerualr diseases. Zhongguo Dang Dai Er Ke Za Zhi, 2009;11(10):866-868.
[91]Haneda M, Koya D, Isono M, et al. Overview of glucose signaling in mesangial cells in diabetic nephropathy. J Am Soc Nephrol,2003; 14: 1374-1382.
[92]Keeling J, Herrera GA. Human matrix metalloproteinases:characteristics and pathologic role in altering mesangial homeostasis. Microsc Res Tech, 2008; 71(5):371-379.
[93]Kanwar YS, Wada J, Sun L, et al. Diabetic nephropathy:mechanisms of renal disease progression. Exp Biol Med (Maywood),2008;233(1):4-11.
[94]Lee HS, Song CY. Differential role of mesangial cells and podocytes in TGF-beta-induced mesangial matrix synthesis in chronic glomerular disease. Histol Histopathol,2009 Jul;24(7):901-908.
[95]Gruden G, Perin PC, Camussi G. Insight on the pathogenesis of diabetic nephropathy from the study of podocyte and mesangial cell biology. Curr Diabetes Rev,2005;1(1):27-40.
[96]Yano N, Suzuki D, Endoh M, et al. High ambient glucose induces angiotensin-independent AT-1 receptor activation, leading to increases in proliferation and extracellular matrix accumulation in MES-13 mesangial cells. Biochem J,2009; 423:129-143.
[97]Matoba K, Kawanami D, Ishizawa S, et al. Rho-kinase mediates TNF-a-induced MCP-1 expression via p38 MAPK signaling pathway in mesangial cells. Biochem Biophys Res Commun,2010; 402(4):725-730.
[98]Lee MJ, Rao YK, Chen K, et al. Andrographolide and 14-deoxy-11,12-didehydroandrographolide from Andrographis paniculata attenuate high glucose-induced fibrosis and apoptosis in murine renal mesangeal cell lines. J Ethnopharmacol,2010;132(2):497-505.
[99]Davis LK, Rodgers BD, Kelley KM. Angiotensin Ⅱ-and glucose-stimulated extracellular matrix production:mediation by the insulin-like growth factor (IGF) axis in a murine mesangial cell line. Endocrine,2008;33(1):32-39.
[100]Cheng DW, Jiang Y, Shalev A, et al. An analysis of high glucose and glucosamine-induced gene expression and oxidative stress in renal mesangial cells. Arch Physiol Biochem,2006; 112(4-5):189-218.
[101]Jiang Y, Cheng DW, Crook ED, et al. Transforming growth factor-beta1 regulation of laminin gamma1 and fibronectin expression and survival of mouse mesangial cells. Mol Cell Biochem,2005;278(1-2):165-175.
[102]Sun J, Xu Y, Deng H, et al. Involvement of osteopontin upregulation on mesangial cells growth and collagen synthesis induced by intermittent high glucose. J Cell Biochem,2010;109(6):1210-21.
[103]Chin HJ, Fu YY, Ahn JM, et al. Omacor, n-3 polyunsaturated fatty acid, attenuated albuminuria and renal dysfunction with decrease of SREBP-1 expression and triglyceride amount in the kidney of type II diabetic animals. Nephrol Dial Transplant,2010;25(5):1450-1457.
[104]Schaeffer V, Hansen KM, Morris DR, et al. Reductions in laminin beta2 mRNA translation are responsible for impaired IGFBP-5-mediated mesangial cell migration in the presence of high glucose. Am J Physiol Renal Physiol,2010;298(2):314-322.
[105]Min D, Lyons JG, Bonner J, et al. Mesangial cell-derived factors alter monocyte activation and function through inflammatory pathways: possible pathogenic role in diabetic nephropathy. Am J Physiol Renal Physiol,2009;297(5):1229-1237.
[106]Taniguchi H, Ebina M, Kondoh Y, et al. Pirfenidone in idiopathic pulmonary fibrosis. Eur Respir J,.2010;35(4):821-829.
[107]Regulatory W, First drug for idiopathic pulmonary fibrosis approved in Japan Nat Rev Drug Discov,2008; 7:966-967.
[108]Armendariz-Borunda J, Islas-Carbajal MC, Meza-Garcia E, et al. A pilot study in patients with established advanced liver fibrosis using pirfenidone. Gut,2006; 55(11):1663-5.
[109]Cho ME, Smith DC, Branton MH, et al. Pirfenidone slows renal function decline in patients with focal segmental glomerulosclerosis. Clin J Am Soc Nephrol,2007; 2(5):876-878.
[110]Walker JE, Giri SN, Margolin SB. A double-blind, randomized, controlled study of oral pirfenidone for treatment of secondary progressive multiple sclerosis. Mult Scler,2005;11(2):149-158.
[111]Foley RN, Collins AJ. End-Stage Renal Disease in the United States:An Update from the United States Renal Data System. J Am Soc Nephrol, 2007;(18):2644-2648.
[112]Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med,2001;345:861-869.
[113]Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med,2001; 345:851-860.
[114]Wu D, Peng F, Zhang B, et al. EGFR-PLCgammal signaling mediates high glucose-induced PKCbetal-Akt activation and collagen I upregulation in mesangial cells. Am J Physiol Renal Physiol, 2009;297(3):822-834.
[115]Pozzi A, Zent R, Chetyrkin S, et al. Modification of collagen IV by glucose or methylglyoxal alters distinct mesangial cell functions. J Am Soc Nephrol.2009; 20(10):2119-2125.
[116]Baccora MH, Cortes P, Hassett C, et al. Effects of long-term elevated glucose on collagen formation by mesangial cells. Kidney Int, 2007;72(10):1216-1225.
[117]Giannico G, Cortes P, Baccora MH, et al. Glibenclamide prevents increased extracellular matrix formation induced by high glucose concentration in mesangial cells. Am J Physiol Renal Physiol,2007; 292(1):57-65.
[118]Pedchenko VK, Chetyrkin SV, Chuang P, et al. Mechanism of perturbation of integrin-mediated cell-matrix interactions by reactive carbonyl compounds and its implication for pathogenesis of diabetic nephropathy. Diabetes,2005; 54(10):2952-2960.
[119]Hayashida T, Schnaper HW. High ambient glucose enhances sensitivity to TGF-betal via extracellular signal--regulated kinase and protein kinase Cdelta activities in human mesangial cells. J Am Soc Nephrol, 2004;15(8):2032-2041.
[120]Li J, Lim SS, Lee ES, et al. Isoangustone A suppresses mesangial fibrosis and inflammation in human renal mesangial cells. Exp Biol Med (Maywood),2011;236(4):435-444.
[121]Xia L, Wang H, Munk S, et al. High glucose activates PKC-zeta and NADPH oxidase through autocrine TGF-betal signaling in mesangial cells. Am J Physiol Renal Physiol,2008;295(6):1705-1714.
[122]Simonson MS. Phenotypic transitions and fibrosis in diabetic nephropathy. Kidney Int,2007;71(9):846-854.
[123]Ziyadeh FN. Mediators of diabetic renal disease:the case for TGF-beta as the major mediator.J Am Soc Nephrol,2004;15 Suppl 1:55-57.
[124]Baricos WH, Cortez SL, Deboisblanc M, et al. Transforming growth factor-beta is a potent inhibitor of extracellular matrix degradation by cultured human mesangial cells. J Am Soc Nephrol,1999;10(4):790-795.
[125]Suzuki D, Miyazaki M, Jinde K, et al. In situ hybridization studies of matrix metalloproteinase-3, tissue inhibitor of metalloproteinase-1 and type IV collagen in diabetic nephropathy. Kidney Int,1997; 52(1):111-119.
[126]Shankland SJ, Ly H, Thai K, et al. Glomerular expression of tissue inhibitor of metalloproteinase (TIMP-1) in normal and diabetic rats. J Am Soc Nephrol,1996;7(1):97-104.
[127]Yang J, Zhou Q, Wang Y, et al. Effect of high glucose on PKC and MMPs/TIMPs in human mesangial cells. Zhong Nan Da Xue Xue Bao Yi Xue Ban,2009; 34(5):425-431.
[128]McLennan SV, Wang XY, Moreno V, et al. Connective tissue growth factor mediates high glucose effects on matrix degradation through tissue inhibitor of matrix metalloproteinase type 1:implications for diabetic nephropathy. Endocrinology,2004;145(12):5646-5655.
[1]Shaw JE, Sicree RA, Zimmet PZ. Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res Clin Pract,2010; 87(1):4-14.
[2]Xu L, Xie X, Wang S, et al. Prevalence of diabetes mellitus in China. Exp Clin Endocrinol Diabetes,2008; 116(1):69-70.
[3]Reutens AT, Atkins RC. Epidemiology of diabetic nephropathy. Contrib Nephrol,2011; 170:1-7.
[4]Kanwar YS, Sun L, Xie P, et al. A glimpse of various pathogenetic mechanisms of diabetic nephropathy. Annu Rev Pathol,2011; 6:395-423.
[5]Fioretto P, Mauer M. Histopathology of diabetic nephropathy. Semin Nephrol. 2007; 27(2):195-207.
[6]Choudhury D, Tuncel M, Levi M. Diabetic nephropathy-a multifaceted target of new therapies. Discov Med,2010; 10(54):406-415.
[7]Ayodele OE, Alebiosu CO, Salako BL. Diabetic nephropathy-a review of the natural history, burden, risk factors and treatment. J Natl Med Assoc,2004; 96(11):1445-1454.
[8]Rossing P, de Zeeuw D. Need for better diabetes treatment for improved renal outcome. Kidney Int Suppl,2011; 120:S28-32.
[9]Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature,2001; 414(6865):813-820.
[10]The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes. N Engl J Med,1993; 329(14):977-986.
[11]UK Prospective Diabetes Study (UKPDS) Group. Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet, 1998; 352(9131):837-853.
[12]Writing Team for the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Sustained effect of intensive treatment of type 1 diabetes mellitus on development and progression of diabetic nephropathy:the Epidemiology of Diabetes Interventions and Complications (EDIC) study. JAMA,2003; 290(16):2159-2167.
[13]Holman RR, Paul SK, Bethel MA, et al.10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med,2008; 359(15):1577-1589.
[14]ADVANCE Collaborative Group, Patel A, MacMahon S, Chalmers J et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med,2008; 358(24):2560-2572.
[15]Raskin P, Allen E, Hollander P, et al. Initiating insulin therapy in type 2 Diabetes:a comparison of biphasic and basal insulin analogs. Diabetes Care, 2005; 28(2):260-265.
[16]Rodbard HW, Jellinger PS, Davidson JA, et al. Statement by an American Association of Clinical Endocrinologists/American College of Endocrinology consensus panel on type 2 diabetes mellitus:an algorithm for glycemic control. Endocr Pract,2009; 15(6):540-559.
[17]The DCCT Research Group. Effect of intensive therapy on the development and progression of diabetic nephropathy in the Diabetes Control and Complications Trial. Kidney Int,1995; 47(6):1702-1720.
[18]The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. N Engl J Med,2000; 342(6):381-389.
[19]Stenvinkel P, Bolinder J, Alvestrand A. Effects of insulin on renal haemodynamics and the proximal and distal tubular sodium handling in healthy subjects. Diabetologia,1992; 35(11):1042-1048.
[20]Rabkin R, Ryan MP, Duckworth WC. The renal metabolism of insulin. Diabetologia,1984; 27(3):351-357.
[21]RaveK, Heise T, Pfutzner A, et al. Impact of diabetic nephropathy on pharmacodynamic and pharmacokinetic properties of insulin in type 1 diabetic patients. Diabetes Care,2001; 24(5):886-890.
[22]BiesenbachG, Raml A, Schmekal B, et al. Decreased insulin requirement in relation to GFR in nephropathic Type 1 and insulin-treated Type 2 diabetic patients. Diabet Med,2003; 20(8):642-645,
[23]Mak RH. Impact of end-stage renal disease and dialysis on glycemic control. Semin Dial,2000; 13(1):4-8.
[24]Reilly JB, Berns JS. Selection and dosing of medications for management of diabetes in patients with advanced kidney disease. Semin Dial,2010; 23(2):163-168.
[25]Mitrakou A. Kidney:its impact on glucose homeostasis and hormonal regulation. Diabetes Res Clin Pract,2011; 93 Suppl 1:S66-72.
[26]Sheldon B, Russell-Jones D, Wright J. Insulin analogues:an example of applied medical science. Diabetes Obes Metab.2009; 11(1):5-19.
[27]Iglesias P, Diez JJ. Insulin therapy in renal disease. Diabetes Obes Metab,2008; 10(10):811-823.
[28]Lyness W, Tyler JF. Lawrence A. Renal impairment does not affect insulin aspart pharmacokinetics in type 1 diabetes. Diabetes,2001; 50 (Suppl.2): A441-A442.
[29]Ciardullo AV, Bacchelli M, Daghio MM, et al. Effectiveness and safety of insulin glargine in the therapy of complicated or secondary diabetes:clinical audit. Acta Diabetol,2006; 43(2):57-60.
[30]Ersoy A, Ersoy C, Altinay T. Insulin analogue usage in a haemodialysis patient with type 2 diabetes mellitus. Nephrol Dial Transplant,2006; 21(2):553-554.
[31]Cavanaugh KL. Diabetes management issues for patients with chronic kidney disease. Clinical Diabetes,2007; 25(3):90-97.
[32]Haneda M, Morikawa A. Which hypoglycaemic agents to use in type 2 diabetic subjects with CKD and how? Nephrol Dial Transplant,2009; 24(2):338-341.
[33]Hasslacher C. Safety and efficacy of repaglinide in type 2 diabetic patients with and without impaired renal function. Diabetes Care,2003; 26(3):886-891.
[34]Sarafidis PA, Stafylas PC, Georgianos PI, et al. Effect of thiazolidinediones on albuminuria and proteinuria in diabetes:a meta-analysis. Am J Kidney Dis, 2010; 55(5):835-847.
[35]Bailey CJ,Turner RC. Metformin. N Engl J Med,1996; 334(9):574-579.
[36]Reilly JB, Berns JS. Selection and dosing of medications for management of diabetes in patients with advanced kidney disease. Semin Dial,2010; 23(2):163-168.
[37]Davidson JA. Incorporating incretin-based therapies into clinical practice: differences between glucagon-like Peptide 1 receptor agonists and dipeptidyl peptidase 4 inhibitors. Mayo Clin Proc,2010; 85(12 Suppl):S27-37.
[38]Kodera R, Shikata K, Kataoka HU, et al. Glucagon-like peptide-1 receptor agonist ameliorates renal injury through its anti-inflammatory action without lowering blood glucose level in a rat model of type 1 diabetes. Diabetologia, 2011;54(4):965-978.
[39]Ishibashi Y, Nishino Y, Matsui T, et al. Glucagon-like peptide-1 suppresses advanced glycation end product-induced monocyte chemoattractant protein-1 expression in mesangial cells by reducing advanced glycation end product receptor level. Metabolism,2011; 60(9):1271-1277.
[40]Liu WJ, Xie SH, Liu YN, et al. Dipeptidyl peptidase (DPP) IV inhibitor attenuates kidney injury in streptozotocin induced diabetic rats. J Pharmacol Exp Ther,2012; 340(2):248-255.
[41]Park CW, Kim HW, Ko SH, et al. Long-term treatment of glucagon-like peptide-1 analog exendin-4 ameliorates diabetic nephropathy through improving metabolic anomalies in db/db mice. J Am Soc Nephrol,2007; 18(4):1227-1238.
[42]Jacobsen LV, Hindsberger C. Robson R, et al. Effect of renal impairment on the pharmaco-kinetics of the GLP-1 analogue liraglutide. Br J Clin Pharmacol, 2009; 68(6):898-905.
[43]Chao EC, Henry RR. SGLT2 inhibition-a novel strategy for diabetes treatment. Nat Rev Drug Discov,2010; 9(7):551-559.
[44]Vallon V, Sharma K. Sodium-glucose transport:role in diabetes mellitus and potential clinical implications. Curr Opin Nephrol Hypertens,2010; 19(5):425-431.
[45]Han S, Hagan DL, Taylor JR, et al. Dapagliflozin, a selective SGLT2 inhibitor, improves glucose homeostasis in normal and diabetic rats. Diabetes,2008; 57(6):1723-1729.
[46]List JF, Woo V, Morales E et al 1. Sodium-glucose cotransport inhibition with dapagliflozin in type 2 diabetes. Diabetes Care,2009; 32(4):650-657.
[47]Bailey CJ, Gross JL, Pieters A, et al. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin:a randomized, double-blind, placebo-controlled trial. Lancet,2010; 375(9733):2223-2233.
[48]48. Tarnow L, Rossing P, Gall MA, et al. Prevalence of arterial hypertension in diabetic patients before and after the JNC-V. Diabetes Care,1994; 17(11): 1247-1251.
[49]Van Buren PN, Toto R. Hypertension in diabetic nephropathy:epidemiology, mechanisms, and management. Adv Chronic Kidney Dis,2011; 18(1):28-41.
[50]Chawla T, Sharma D, Singh A. Role of the renin angiotensin system in diabetic nephropathy. World J Diabetes,2010; 1(5):141-145.
[51]Gnudi L, Thomas SM, Viberti G. Mechanical forces in diabetic kidney disease: a trigger for impaired glucose metabolism. J Am Soc Nephrol,2007; 18:2226-2232.
[52]Mogensen CE. Progression of nephropathy in long-term diabetics with proteinuria and effect of initial anti-hypertensive treatment. Scand J Clin Lab Invest,1976; 36:383-388.
[53]Kasiske BL, Kalil RS, Ma JZ, et al. Effect of antihypertensive therapy on the kidney in patients with diabetes:a meta-regression analysis. Ann Intern Med, 1993; 118(2):129-138.
[54]Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med,2001; 345(12):851-860.
[55]Lewis EJ, Hunsicker LG, Bain RP, et al. The effect of angiotensin converting enzyme inhibition on diabetic nephropathy. N Engl J Med,329(20):1456-1462.
[56]Kvetny J, Gregersen G, Pedersen RS. Randomized placebo-controlled trial of perindopril in normotensive, normoalbuminuric patients with type 1 diabetes mellitus. QJM.2001; 94(2):89-94.
[57]Viberti G, Wheeldon NM. Microalbuminuria reduction with valsartan in patients with type 2 diabetes mellitus:a blood pressure-independent effect. Circulation,2002; 106(6):672-678.
[58]Thurman JM, Schrier RW. Comparative effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on blood pressure and the kidney. Am J Med,2003; 114(7):588-598.
[59]Shammas NW, Sica DA, Toth PP. A guide to the management of blood pressure in the diabetic hypertensive patient. Am J Cardiovasc Drugs,2009; 9(3):149-162.
[60]Mogensen CE, Neldam S, Tikkanen I, et al. Randomised controlled trial of dual blockade of renin-angiotensin system in patients with hypertension, microalbuminuria, and non-insulin dependent diabetes:the candesartan and lisinopril microalbuminuria (CALM) study. BMJ,2000; 321(7274):1440-1444.
[61]Jacobsen P, Rossing K, Parving HH. Single versus dual blockade of the renin-angiotensin system (angiotensin-converting enzyme inhibitors and/or angiotensin Ⅱ receptor blockers) in diabetic nephropathy. Curr Opin Nephrol Hypertens,2004; 13(3):319-324.
[62]Sato A, Hayashi K, Naruse M, et al. Effectiveness of aldosterone blockade in patients with diabetic nephropathy. Hypertension,2003; 41(1):64-68.
[63]Daugherty KK. Aliskiren. Am J Health Syst Pharm,2008; 65(14):1323-1332.
[64]Miiller DN, Luft FC. Direct renin inhibition with aliskiren in hypertension and target organ damage.Clin J Am Soc Nephrol,2006; 1(2):221-228.
[65]Kelly DJ, Zhang Y, Moe G, et al. Aliskiren, a novel renin inhibitor, is renoprotective in a model of advanced diabetic nephropathy in rats. Diabetologia,2007; 50(11):2398-2404.
[66]Phillips LM, Wang Y, Dai T, et al. The renin inhibitor aliskiren attenuates high-glucose induced extracellular matrix synthesis and prevents apoptosis in cultured podocytes. Nephron Exp Nephrol,2011; 118(3):e49-59.
[67]Persson F, Rossing P, Schjoedt KJ, et al. Time course of the antiproteinuric and anti-hypertensive effects of direct renin inhibition in type 2 diabetes. Kidney Int,2008; 73(12):1419-1425.
[68]Persson F, Lewis JB, Lewis EJ, et al. Impact of baseline renal function on the efficacy and safety of aliskiren added to losartan in patients with type 2 diabetes and nephropathy. Diabetes Care,2010; 33(11):2304-2309.
[69]Persson F, Lewis JB, Lewis EJ, et al. Aliskiren in combination with losartan reduces albuminuria independent of baseline blood pressure in patients with type 2 diabetes and nephropathy. Clin J Am Soc Nephrol,2011; 6(5):1025-1031.
[70]Yusuf S, Teo KK, Pogue J, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med,2008; 358(15):1547-1559.
[71]Zhang D, Gu T, Forsberg E, et al. Genetic and functional effects of membrane metallo-endopeptidase on diabetic nephropathy development. Am J Nephrol, 2011;34(5):483-490.
[72]Quaschning T. Vasopeptidase inhibition for blood pressure control:emerging experience. Curr Pharm Des,2005;11(25):3293-3299.
[73]Houlihan CA, Allen TJ, Baxter AL et al. A low-sodium diet potentiates the effects of losartan in type 2 diabetes. Diabetes Care,2002; 25(4):663-671.
[74]Taal MW, Nenov VD, Wong W, et al. Vasopeptidase inhibition affords greater renoprotection than angiotensin-converting enzyme inhibition alone. J Am Soc Nephrol,2001; 12(10):2051-2059.
[75]Russell JC, Kelly SE, Schafer S. Vasopeptidase inhibition improves insulin sensitivity and endothelial function in the JCR:LA-cp rat. J Cardiovasc Pharmacol,2004; 44(2):258-265.
[76]Davis BJ, Johnston CI, Burrell LM, et al. Renoprotective effects of vasopeptidase inhibition in an experimental model of diabetic nephropathy. Diabetologia,2003; 46(7):961-971.
[77]Cheng ZJ, Gronholm T, Louhelainen M, et al. Vascular and renal effects of vasopeptidase inhibition and angiotensin-converting enzyme blockade in spontaneously diabetic Goto-Kakizaki rats. J Hypertens,2005; 23(9):1757-1770.
[78]Fredersdorf S, Weil J, Ulucan C, et al. Vasopeptidase inhibition attenuates proteinuria and podocyte injury in Zucker diabetic fatty rats. Naunyn Schmiedebergs Arch Pharmacol,2007; 375(2):95-103.
[79]Schafer S, Linz W, Bube A, et al. Vasopeptidase inhibition prevents nephropathy in Zucker diabetic fatty rats. Cardiovasc Res,2003; 60(2):447-454.
[80]Portero-Otin M, Pamplona R, Boada J, et al. Inhibition of renin angiotensin system decreases renal protein oxidative damage in diabetic rats. Biochem Biophys Res Commun,2008; 368(3):528-535.
[81]Gross O, Koepke ML, Beirowski B, et al. Nephroprotection by antifibrotic and anti-inflammatory effects of the vasopeptidase inhibitor AVE7688. Kidney Int, 2005; 68(2):456-463.
[82]Tikkanen T, Tikkanen I, Rockell MD, et al. Dual inhibition of neutral endopeptidase and angiotensin-converting enzyme in rats with hypertension and diabetes mellitus. Hypertension,1998; 32(4):778-785.
[83]Azizi M, Bissery A, Peyrard S, et al. Pharmacokinetics and pharmacodynamics of the vasopeptidase inhibitor AVE7688 in humans. Clin Pharmacol Ther,2006; 79(1):49-61.
[84]Rousso P, Buclin T, Nussberger J, et al. Effects of a dual inhibitor of angiotensin converting enzyme and neutral endopeptidase, MDL 100,240, on endocrine and renal functions in healthy volunteers. J Hypertens,1999; 17(3):427-437.
[85]Liao WC, Vesterqvist O, Delaney C, et al. Pharmacokinetics and pharmacodynamics of the vasopeptidase inhibitor, omapatrilat in healthy subjects. Br J Clin Pharmacol,2003; 56(4):395-406.
[86]Regamey F, Maillard M, Nussberger J, et al. Renal hemodynamic and natriuretic effects of concomitant Angiotensin-converting enzyme and neutral endopeptidase inhibition in men. Hypertension,2002; 40(3):266-272.
[87]Azizi M, Lamarre-Cliche M, Labatide-Alanore A, et al. Physiologic consequences of vasopeptidase inhibition in humans:effect of sodium intake. J Am Soc Nephrol,2002; 13(10):2454-2463.
[88]Liao W, Delaney CL, Catanzariti PA, et al. Omapatrilat is not a diuretic: single-and multipledose analysis of the urinary excretion of sodium. Am J Hypertens,2000; 13:133A(abstract).
[89]Campese VM, Lasseter KC, Ferrario CM et al. Omapatrilat versus lisinopril: efficacy and neurohormonal profile in saltsensitive hypertensive patients. Hypertension,2000; 38(6):1342-1348.
[90]Kostis JB, Packer M, Black HR et al. Omapatrilat and enalapril in patients with hypertension:the Omapatrilat Cardiovascular Treatment vs. Enalapril (OCTAVE) trial. Am J Hypertens,2004; 17:103-111.
[91]Dimitropoulos N, Papakyriakou A, Dalkas GA, et al. A computational approach to the study of the binding mode of dual ACE/NEP inhibitors. J Chem Inf Model,2010; 50(3):388-396.
[92]Maahs DM, Ogden LG, Dabelea D, et al. Association of glycaemia with lipids in adults with type 1 diabetes:modification by dyslipidaemia medication. Diabetologia,2010; 53(12):2518-2525.
[93]Bell DS, Al Badarin F, O'Keefe JH Jr. Therapies for diabetic dyslipidaemia. Diabetes Obes Metab.2011; 13(4):313-325.
[94]Mazzone T, Chait A, Plutzky J. Cardiovascular disease risk in type 2 diabetes mellitus:insights from mechanistic studies. Lancet,2008; 371(9626):1800-1819.
[95]Moorhead JF, Chan MK, El-Nahas M, et al. Lipid nephrotoxicity in chronic progressive glomerular and tubulointerstitial disease. Lancet,1982; 320(8311):1309-1311.
[96]Ravid M, Brosh D, Ravid-Safran D, et al. Main risk factors for nephropathy in type 2 diabetes mellitus are plasma cholesterol levels, mean blood pressure, and hyperglycemia. Arch Intern Med,1998; 158(9):998-1004.
[97]Palmer BE, Alpern RJ. Treating dyslipidemia to slow the progression of chronic renal failure. Am J Med,2003; 114(5):411-412.
[98]Eddy AA, Liu E, McCulloch L. Interstitial fibrosis in hypercholesterolemic rats: role of oxidation, matrix synthesis, and proteolytic cascades. Kidney Int,1998; 53(5):1182-1189.
[99]Pai R, Kirschenbaum MA, Kamanna VS. Low-density lipoprotein stimulates the expression of macrophage colony-stimulating factor in glomerular mesangial cells. Kidney Int,1995; 48(4):1254-1262.
[100]Haffner SM. Statin therapy for the treatment of diabetic dyslipidemia. Diabetes Metab Res Rev,2003; 19(4):280-287.
[101]Fellstrom, BC, Jardine AG, Schmieder RE, et al. Rosuvastatin and cardiovascular events in patients undergoing hemodialysis. N Engl J Med,2009; 360(14):1395-1407.
[102]Tonelli M, Moye L, Sacks FM, et al. Cholesterol and Recurrent Events (CARE) Trial Investigators. Pravastatin for secondary prevention of cardiovascular events in persons with mild chronic renal insufficiency. Ann Intern Med,2003; 138(2):98-104.
[103]Kostapanos MS, Liberopoulos EN, Elisaf MS. Statin pleiotropy against renal injury. J Cardiometab Syndr.2009; 4(1):E4-9.
[104]Usui H, Shikata K, Matsuda M, et al. HMG-CoA reductase inhibitor ameliorates diabetic nephropathy by its pleiotropic effects in rats. Nephrol Dial Transplant,2003; 18(2):265-272.
[105]Wei P, Grimm PR, Settles DC, et al. Simvastatin reverses podocyte injury but not mesangial expansion in early stage type 2 diabetes mellitus. Ren Fail,2009; 31(6):503-513.
[106]Tamura Y, Murayama T, Minami M, et al. Differential effect of statins on diabetic nephropathy in db/db mice. Int J Mol Med,2011; 28(5):683-687.
[107]Abe M, Maruyama N, Okada K, et al. Effects of lipid-lowering therapy with rosuvastatin on kidney function and oxidative stress in patients with diabetic nephropathy. J Atheroscler Thromb,2011; 18(11):1018-1028.
[108]Danesh FR, Kanwar YS. Modulatory effects of HMG-CoA reductase inhibitors in diabetic microangiopathy. FASEB J,2004; 18(7):805-815.
[109]Sandhu S, Wiebe N, Fried LF, et al. Statins for improving renal outcomes:a metaanalysis. J Am Soc Nephrol,2006; 17(7):2006-2016.
[110]Colhoun HM, Betteridge DJ, Durrington PN, et al. Effects of atorvastatin on kidney outcomes and cardiovascular disease in patients with diabetes:an analysis from the Collaborative Atorvastatin Diabetes Study (CARDS). Am J Kidney Dis,2009; 54(5):810-819.
[111]Keating GM. Fenofibrate. A review of its lipid-modifying effects in dyslipidemia and its vascular effects in type 2 diabetes mellitus. Am J Cardiovasc Drugs,2011;11(4):227-247.
[112]Park CW, Zhang Y, Zhang X, et al. PPARalpha agonist fenofibrate improves diabetic nephropathy in db/db mice. Kidney Int,2006; 69(9):1511-1517.
[113]Li L, Emmett N, Mann D, et al. Fenofibrate attenuates tubulointerstitial fibrosis and inflammation through suppression of nuclear factor-KB and transforming growth factor-β1/Smad3 in diabetic nephropathy. Exp Biol Med (Maywood), 2010; 235(3):383-391.
[114]Tanaka Y, Kume S, Araki S, et al. Fenofibrate, a PPARa agonist, has renoprotective effects in mice by enhancing renal lipolysis. Kidney Int.2011; 79(8):871-882.
[115]Ansquer JC, Foucher C, Rattier S, et al; DAIS Investigators. Fenofibrate reduces progression to microalbuminuria over 3 years in a placebo-controlled study in type 2 diabetes:results from the Diabetes Atherosclerosis Intervention Study (DAIS). Am J Kidney Dis,2005; 45(3):485-493.
[116]The FIELD Study Investigators. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (The FIELD study):randomised controlled trial. Lancet,2005; 366(3):1849-1861.
[117]Davis TM, Ting R, Best JD, et al. FIELD Study investigators. Effects of fenofibrate on renal function in patients with type 2 diabetes mellitus:the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study. Diabetologia,2011; 54(2):280-290.
[118]Forsblom C, Hiukka A, Leinonen ES, et al. Effects of long-term fenofibrate treatment on markers of renal function in type 2 diabetes:the FIELD Helsinki substudy. Diabetes Care,2010; 33(2):215-220.
[119]Ginsberg HN, Elam MB, Lovato LC, et al. Effects of Combination Lipid Therapy in Type 2 Diabetes Mellitus. N Engl J Med,2010; 362(17):1563-1574.
[120]Farnier M, Steinmetz A, Retterst(?)l K, et al. Fixed-dose combination fenofibrate/pravastatin 160/40 mg versus simvastatin 20 mg monotherapy in adults with type 2 diabetes and mixed hyperlipidemia uncontrolled with simvastatin 20 mg:a double-blind, randomized comparative study. Clin Ther, 2011;33(1):1-12.
[121]Arora MK, Reddy K, Balakumar P. The low dose combination of fenofibrate and rosiglitazone halts the progression of diabetes-induced experimental nephropathy. Eur J Pharmacol,2010; 636(1-3):137-144.
[122]Frank C. Brosius III. New insights into the mechanisms of fibrosis and sclerosis in diabetic nephropathy. Rev Endocr Metab Disord,2008; 9(4):245-254.
[123]Pinzani, M. Antifibrotic Drugs, in Portal Hypertension V:Proceedings of the Fifth Baveno International Consensus Workshop, Fifth Edition (ed de Franchis R), Wiley-Blackwell, Oxford, UK,2011,211-217
[124]Richeldi L, Yasothan U, Kirkpatrick P. Pirfenidone. Nat Rev Drug Discov, 2011; 10(7):489-490.
[125]Iyer SN, Wild JS, Schiedt MJ, et al. Dietary intake of pirfenidone ameliorates bleomycin-induced lung fibrosis in hamsters. J Lab Clin Med,1995; 125(6):779-785.
[126]Hewitson TD, Kelynack KJ, Tait MG, et al. Pirfenidone reduces in vitro rat renal fibroblast activation and mitogenesis. J Nephrol,2001; 14(6):453-460.
[127]Shimizu T, Kuroda T, Hata S, et al. Pirfenidone improves renal function and fibrosis in the post-obstructed kidney. Kidney Int,1998; 54(1):99-109.
[128]Leh S, Vaagnes O, Margolin SB, et al. Pirfenidone and candesartan ameliorate morphological damage in mild chronic anti-GBM nephritis in rats. Nephrol Dial Transplant,2005; 20(1):71-82.
[129]Miric G, Dallemagne C, Endre Z, et al. Reversal of cardiac and renal fibrosis by pirfenidone and spironolactone in streptozotocin-diabetic rats. Br J Pharmacol,2001; 133(5):687-694.
[130]Ramachandra Rao SP, Zhu Y, Ravasi T, et al. Pirfenidone is renoprotective in diabetic kidney disease. J Am Soc Nephrol,2009; 20(8):1765-1775.
[131]Cho ME, Smith DC, Branton MH, et al. Pirfenidone slows renal function decline in patients with focal segmental glomerulosclerosis. Clin J Am Soc Nephrol,2007; 2(5):906-913.
[132]Lao LJ, Hu GY, Shi YE. Composition and method for treating fibrotic diseases: US 2009/0258911 A1[P].2009-10-15
[133]Yuan Q, Wang R, Peng Y, et al. Fluorofenidone attenuates tubulointerstitial fibrosis by inhibiting TGF-β(1)-induced fibroblast activation. Am J Nephrol, 2011; 34(2):181-94.
[134]Li BX, Tang YT, Wang W, et al. Fluorofenidone attenuates renal interstitial fibrosis in the rat model of obstructive nephropathy. Mol Cell Biochem.2011; 354(1-2):263-273.
[135]Tao LJ, Zhang J, Hu GY. Effects of 1-(3-fluorophenyl)-5-methyl-2-(1H)-pyridone on renal fibroblast in rats. Zhong Nan Da Xue Xue Bao Yi Xue Ban, 2004;29(2):139-141.
[136]Wang L, Hu GY, Shen H, et al. Fluorofenidone inhibits TGF-betal induced CTGF via MAPK pathways in mouse mesangial cells. Pharmazie,2009; 64(10):680-684.
[137]Peng ZZ, Hu GY, Shen H, et al. Fluorofenidone attenuates collagen I and transforming growth factor-beta1 expression through a nicotinamide adenine dinucleotide phosphate oxidase-dependent way in NRK-52E cells. Nephrology (Carlton),2009; 14(6):565-572.
[138]Wang LH, Liu JS, Ning WB, et al. Fluorofenidone attenuates diabetic nephropathy and kidney fibrosis in db/db mice. Pharmacology,2011; 88(1-2):88-99.
[139]Sugaru E, Sakai M, Horigome K, et al. SMP-534 inhibits TGF-beta-induced ECM production in fibroblast cells and reduces mesangial matrix accumulation in experimental glomerulonephritis. Am J Physiol Renal Physiol,2005; 289(5):F998-1004.
[140]Sugaru E, Nakagawa T, Ono-Kishino M, et al. SMP-534 ameliorates progression of glomerular fibrosis and urinary albumin in diabetic db/db mice. Am J Physiol Renal Physiol.2006; 290(4):F813-820.
[141]Sugaru E, Nakagawa T, Ono-Kishino M, et al. Amelioration of established diabetic nephropathy by combined treatment with SMP-534 (antifibrotic agent) and losartan in db/db mice. Nephron Exp Nephrol,2007; 105(2):e45-52.
[142]Hirano T, Kashiwazaki K, Moritomo Y, et al. Albuminuria is directly associated with increased plasma PAI-1 and factor VII levels in NIDDM patients. Diabetes Res Clin Pract.1997; 36(1):11-18.
[143]Seo JY, Park J, Yu MR, et al. Positive feedback loop between plasminogen activator inhibitor-1 and transforming growth factor-betal during renal fibrosis in diabetes. Am J Nephrol,2009; 30(6):481-490.
[144]Rerolle JP, Hertig A, Nguyen G, et al. Plasminogen activator inhibitor type 1 is a potential target in renal fibrogenesis. Kidney Int,2000; 58(5):1841-1850.
[145]Izuhara Y, Takahashi S, Nangaku M, et al. Inhibition of plasminogen activator inhibitor-1:its mechanism and effectiveness on anticoagulation and anti-fibrosis. Arterioscler Thromb Vasc Biol,2008; 28(4):672-677.
[146]Huang Y, Border WA, Yu L, et al. A PAI-1 mutant, PAI-1R, slows progression of diabetic nephropathy. J Am Soc Nephrol,2008; 19(2):329-338.
[147]Cheng H, Fan X, Moeckel GW, et al. Podocyte COX-2 exacerbates diabetic nephropathy by increasing podocyte (pro)rennin receptor expression. J Am Soc Nephrol,2011; 22(7):1240-1251.
[148]Zhou QL, Peng WS, Yuichiro Y, et al. Effect of losartan on cyclooxygenase-2 expression in normal human mesangial cells and kidneys of rats with diabetic nephropathy. Zhong Nan Da Xue Xue Bao Yi Xue Ban,2008; 33(9):790-799.
[149]Ko GJ, Kang YS, Han SY, et al. Pioglitazone attenuates diabetic nephropathy through an anti-inflammatory mechanism in type 2 diabetic rats. Nephrol Dial Transplant.2008; 23(9):2750-2760.
[150]Radfar M, Larijani B, Hadjibabaie M, et al. Effects of pentoxifylline on oxidative stress and levels of EGF and NO in blood of diabetic type-2 patients; a randomized, double-blind placebo-controlled clinical trial. Biomed Pharmacother,2005; 59(6):302-306.
[151]Sinzinger H. Pentoxifylline enhances formation of prostacyclin from rat vascular and renal tissue. Prostaglandins Leukot Med,1983; 12(2):217-226.
[152]Han KH, Han SY, Kim HS, et al. Prolonged administration enhances the renoprotective effect of pentoxifylline via anti-inflammatory activity in streptozotocin-induced diabetic nephropathy. Inflammation,2010; 33(3):137-143.
[153]Chen YM, Lin SL, Chiang WC, et al. Pentoxifylline ameliorates proteinuria through suppression of renal monocyte chemoattractant protein-1 in patients with proteinuric primary glomerular diseases. Kidney Int,2006; 69(8):1410-1415.
[154]Badri S, Dashti-Khavidaki S, Lessan-Pezeshki M, et al. A review of the potential benefits of pentoxifylline in diabetic and non-diabetic proteinuria. J Pharm Pharm Sci,2011; 14(1):128-137.
[155]McCormick BB, Sydor A, Akbari A, et al. The effect of pentoxifylline on proteinuria in diabetic kidney disease:a meta-analysis. Am J Kidney Dis,2008; 52(3):454-463.
[156]Navarro-Gonzalez JF, Muros M, Mora-Fernandez C, et al. Pentoxifylline for Renoprotection in Diabetic Nephropathy:the PREDIAN study. Rationale and basal results. J Diabetes Complications,2011; 25(5):314-319.
[157]Chakraborti AK, Garg SK, Kumar R, et al. Progress in COX-2 inhibitors:a journey so far. Curr Med Chem,2010; 17(15):1563-1593.
[158]Hao CM, Breyer MD. Physiologic and pathophysiologic roles of lipid mediators in the kidney. Kidney Int,2007; 71(11):1105-1115.
[159]Yabuki A, Taniguchi K, Yamato O. Immunohistochemical examination of cyclooxygenase-2 and renin in a KK-A(y) mouse model of diabetic nephropathy. Exp Anim,2010; 59(4):479-486.
[160]Quilley J, Santos M, Pedraza P. Renal protective effect of chronic inhibition of COX-2 with SC-58236 in streptozotocin-diabetic rats. Am J Physiol Heart Circ Physiol,2011; 300(6):H2316-2322.
[161]Cheng HF, Wang CJ, Moeckel GW, et al. Cyclooxygenase-2 inhibitor blocks expression of mediators of renal injury in a model of diabetes and hypertension. Kidney Int,2002; 62(3):929-939.
[162]Komers R, Lindsley JN, Oyama TT, et al. Cyclo-oxygenase-2 inhibition attenuates the progression of nephropathy in uninephrectomized diabetic rats. Clin Exp Pharmacol Physiol,2007; 34(1-2):36-41.
[163]Sinsakul M, Sika M, Rodby R, et al. A randomized trial of a 6-week course of celecoxib on proteinuria in diabetic kidney disease. Am J Kidney Dis,2007; 50(6):946-951.
[164]Cherney DZ, Miller JA, Scholey JW, et al. The effect of cyclooxygenase-2 inhibition on renal hemodynamic function in humans with type 1 diabetes. Diabetes,2008; 57(3):688-695.
[165]Giacco F, Brownlee M. Oxidative stress and diabetic complications. Circ Res, 2010; 107(9):1058-1070.
[166]Ceriello A, Morocutti A, Mercuri F, et al. Defective intracellular antioxidant enzyme production in type 1 diabetic patients with nephropathy. Diabetes,2000; 49(12):2170-2177.
[167]Farvid MS, Jalali M, Siassi F, et al. Comparison of the effects of vitamins and/or mineral supplementation on glomerular and tubular dysfunction in type 2 diabetes. Diabetes Care,2005; 28(10):2458-2464.
[168]Gaede P, Poulsen HE, Parving HH, et al. Double-blind, randomized study of the effect of combined treatment with vitamin C and E on albuminuria in Type 2 diabetic patients. Diabet Med,2001;18(9):756-760.
[169]Mann JF, Lonn EM, Yi Q, et al. Effects of vitamin E on cardiovascular outcomes in people with mild-to-moderate renal insufficiency:results of the HOPE study. Kidney Int,2004; 65(4):1375-1380.
[170]Endo K, Miyashita Y, Sasaki H, et al. Probucol delays progression of diabetic nephropathy. Diabetes Res Clin Pract,2006; 71(2):156-163.
[171]Goicoechea M, de Vinuesa SG, Verdalles U, et al. Effect of allopurinol in chronic kidney disease progression and cardiovascular risk. Clin J Am Soc Nephrol,2010; 5(8):1388-1393.
[172]Morcos M, Borcea V, Isermann B, et al. Effect of alpha-lipoic acid on the progression of endothelial cell damage and albuminuria in patients with diabetes mellitus:an exploratory study. Diabetes Res Clin Pract,2001; 52(3):175-183.
[173]Zibadi S, Rohdewald PJ, Park D, et al. Reduction of cardiovascular risk factors in subjects with type 2 diabetes by Pycnogenol supplementation. Nutr Res, 2008; 28(5):315-320.
[174]Kadhim HM, Ismail SH, Hussein KI, et al. Effects of melatonin and zinc on lipid profile and renal function in type 2 diabetic patients poorly controlled with metformin, J Pineal Res 2006; 41(2):189-193.
[175]Kim HJ, Vaziri ND. Contribution of impaired Nrf2-Keapl pathway to oxidative stress and inflammation in chronic renal failure. Am J Physiol Renal Physiol,2010; 298(3):F662-F671.
[176]Pergola PE, Raskin P, Toto RD, et al. Bardoxolone methyl and kidney function in CKD with type 2 diabetes. N Engl J Med,2011; 365(4):327-336.
[177]Tojo A, Asaba K, Onozato ML. Suppressing renal NADPH oxidase to treat diabetic nephropathy. Expert Opin Ther Targets,2007; 11(8):1011-1018.
[178]Thallas-Bonke V, Coughlan MT, Bach LA, et al. Preservation of kidney function with combined inhibition of NADPH oxidase and angiotensin-converting enzyme in diabetic nephropathy. Am J Nephrol 2010; 32(1):73-82.
[179]Asaba K, Tojo A, Onozato ML, et al. Effects of NADPH oxidase inhibitor in diabetic nephropathy. Kidney Int,2005; 67(5):1890-1898.
[180]Shi XY, Hou FF, Niu HX, et al. Advanced oxidation protein products promote inflammation in diabetic kidney through activation of renal nicotinamide adenine dinucleotide phosphate oxidase. Endocrinology 2008; 149(4):1829-1839.
[181]Ahmad A, Mondello S, Di Paola R, et al. Protective effect of apocynin, a NADPH-oxidase inhibitor, against contrast-induced nephropathy in the diabetic rats:A comparison with n-acetylcysteine. Eur J Pharmacol,2012; 674(2-3):397-406.
[182]DeRubertis FR, Craven PA, Melhem MF. Acceleration of diabetic renal injury in the superoxide dismutase knockout mouse:effects of tempol. Metabolism. 2007; 56(9):1256-1264.
[183]Fujita H, Fujishima H, Chida S, et al. Reduction of renal superoxide dismutase in progressive diabetic nephropathy. J Am Soc Nephrol,2009; 20(6):1303-1313.
[184]Peixoto EB, Pessoa BS, Biswas SK, et al. Antioxidant SOD mimetic prevents NADPH oxidase-induced oxidative stress and renal damage in the early stage of experimental diabetes and hypertension. Am J Nephrol,2009; 29(4):309-318.
[185]Rodriguez F, Lopez B, Perez C, et al. Chronic tempol treatment attenuates the renal hemodynamic effects induced by a heme oxygenase inhibitor in streptozotocin diabetic rats. Am J Physiol Regul Integr Comp Physiol 2011; 301(5):R1540-1548.
[186]Nassar T, Kadery B, Lotan C, et al. Effects of the superoxide dismutase-mimetic compound tempol on endothelial dysfunction in streptozotocin-induced diabetic rats. Eur J Pharmacol,2002; 436(1-2):111-118.
[187]Asaba K, Tojo A, Onozato ML, et al. Double-edged action of SOD mimetic in diabetic nephropathy. J Cardiovasc Pharmacol 2007; 49(1):13-19.
[188]Juhasz B, Varga B, Gesztelyi R, et al. Resveratrol:a multifunctional cytoprotective molecule. Curr Pharm Biotechnol,2010; 11(8):810-818.
[189]Sharma S, Anjaneyulu M, Kulkarni SK, et al 1. Resveratrol, a polyphenolic phyto-alexin, attenuates diabetic nephropathy in rats. Pharmacology,2006; 76(2):69-75.
[190]Kitada M, Kume S, Imaizumi N, et al. Resveratrol improves oxidative stress and protects against diabetic nephropathy through normalization of Mn-SOD dysfunction in AMPK/SIRT1-independent pathway. Diabetes,2011; 60(2):634-643.
[191]Chang CC, Chang CY, Wu YT, et al. Resveratrol retards progression of diabetic nephropathy through modulations of oxidative stress, proinflammatory cytokines, and AMP-activated protein kinase. J Biomed Sci.2011; 18(1):47-57.
[192]Ding DF, You N, Wu XM, et al. Resveratrol attenuates renal hypertrophy in early-stage diabetes by activating AMPK. Am J Nephrol,2010; 31(4):363-374.
[193]Tikoo K, Singh K, Kabra D, et al. Change in histone H3 phosphorylation, MAP kinase p38, SIR 2 and p53 expression by resveratrol in preventing streptozotocin induced type I diabetic nephropathy. Free Radic Res,2008; 42(4):397-404.
[194]Singh R, Barden A, Mori T, Beilin L. Advanced glycation end-products:a review. Diabetologia,2001; 44(2):129-146.
[195]Reiniger N, Lau K, McCalla D, et al. Deletion of the receptor for advanced glycation end products reduces glomerulosclerosis and preserves renal function in the diabetic OVE26 mouse. Diabetes,2010; 59(8):2043-2054.
[196]Forbes JM, Cooper ME, Oldfield MD, Thomas MC.2003. Role of advanced glycation end products in diabetic nephropathy. J Am Soc Nephrol, 14:S254-258
[197]Yamagishi S, Matsui T. Advanced glycation end products, oxidative stress and diabetic nephropathy. Oxid Med Cell Longev,2010; 3(2):101-108.
[198]Abdel-Rahman E, Bolton WK. Pimagedine:a novel therapy for diabetic nephropathy. Expert Opin Investig, Drugs,2002;11(4):565-574.
[199]Bolton WK, Cattran DC, Williams ME, et al. Randomized trial of an inhibitor of formation of advanced glycation end products in diabetic nephropathy. Am J Nephrol,2004;24(1):32-40.
[200]Suji G, Sivakami S. DNA damage by free radical production by aminoguanidine. Ann N Y Acad Sci,2006; 1067:191-199.
[201]Chetyrkin SV, Zhang W, Hudson BG, et al. Pyridoxamine protects proteins from functional damage by 3-deoxyglucosone:mechanism of action of pyridoxamine. Biochemistry,2008; 47(3):997-1006.
[202]Alderson NL, Chachich ME, Youssef NN, et al. The AGE inhibitor pyridoxamine inhibits lipemia and development of renal and vascular disease in Zucker obese rats. Kidney Int,2003; 63(6):2123-2133.
[203]Tanimoto M, Gohda T, Kaneko S, et al. Effect of pyridoxamine (K-163), an inhibitor of advanced glycation end products, on type 2 diabetic nephropathy in KK-A(y)/Ta mice. Metabolism,2007; 56(2):160-167.
[204]Williams ME, Bolton WK, Khalifah RG, et al. Effects of pyridoxamine in combined phase 2 studies of patients with type 1 and type 2 diabetes and overt nephropathy. Am J Nephrol,2007; 27(6):605-614.
[205]Pacal L, Tomandl J, Svojanovsky J, et al. Role of thiamine status and genetic variability in transketolase and other pentose phosphate cycle enzymes in the progression of diabetic nephropathy. Nephrol Dial Transplant,2011; 26(4):1229-1236.
[206]Babaei-Jadidi R, Karachalias N, Kupich C, et al. High dose thiamine therapy counters dyslipidaemia in streptozotocin-induced diabetic rats. Diabetologia, 2004;47(12):2235-2246.
[207]Rabbani N, Alam SS, Riaz S, et al. High-dose thiamine therapy for patients with type 2 diabetes and microalbuminuria:a randomised, double-blind placebo-controlled pilot study. Diabetologia,2009; 52(2):208-212.
[208]Riaz S, Skinner V, Srai SK. Effect of high dose thiamine on the levels of urinary protein biomarkers in diabetes mellitus type 2. J Pharm Biomed Anal, 2011; 54(4):817-825.
[209]Balakumar P, Rohilla A, Krishan P, et al. The multifaceted therapeutic potential of benfotiamine. Pharmacol Res,2010; 61(6):482-488.
[210]Babaei-Jadidi R, Karachalias N, Ahmed N, et al. Prevention of incipient diabetic nephropathy by high-dose thiamine and benfotiamine. Diabetes,2003; 52(8):2110-2120.
[211]Alkhalaf A, Klooster A, van Oeveren W, et al. A double-blind, randomized, placebo-controlled clinical trial on benfotiamine treatment in patients with diabetic nephropathy. Diabetes Care,2010; 33(1):1598-1601.
[212]Wilkinson-Berka JL, Kelly DJ, Koerner SM, et al. ALT-946 and aminoguanidine, inhibitors of advanced glycation, improve severe nephropathy in the diabetic transgenic (mREN-2)27 rat. Diabetes,2002; 51(11):3283-3289.
[213]Goh SY, Jasik M, Cooper ME. Agents in development for the treatment of diabetic nephropathy. Expert Opin Emerg Drugs,2008; 13(3):447-463.
[214]Vasan S, Zhang X, Zhang X, et al. An agent cleaving glucose-derived protein crosslinks in vitro and in vivo. Nature,1996; 382(6588):275-278.
[215]Peppa M, Brem H, Cai W, et al. Prevention and reversal of diabetic nephropathy in db/db mice treated with alagebrium (ALT-711). Am J Nephrol, 2006; 26(5):430-436.
[216]Coughlan MT, Forbes JM, Cooper ME. Role of the AGE crosslink breaker, alagebrium, as a renoprotective agent in diabetes. Kidney Int Suppl,2007; 106:S54-60.
[217]Kass DA, Shapiro EP, Kawaguchi M, et al. Improved arterial compliance by a novel advanced glycation endproduct crosslink breaker. Circulation,2001; 104(13):1464-1470.
[218]Zieman SJ, Melenovsky V, Clattenburg L, et al. Advanced glycation endproduct crosslink breaker (alagebrium) improves endothelial function in patients with isolated systolic hypertension. J Hypertens,2007; 25(3):577-583.
[219]Hartog JW, Willemsen S, van Veldhuisen DJ, et al. Effects of alagebrium, an advanced glycation endproduct breaker, on exercise tolerance and cardiac function in patients with chronic heart failure. Eur J Heart Fail,2011; 13(8):899-908.
[220]Joshi D, Gupta R, Dubey A, et al. TRC4186, a novel AGE-breaker, improves diabetic cardiomyopathy and nephropathy in ob-ZSF1 model of type 2 diabetes. J Cardiovasc Pharmacol,2009; 54(1):72-81.
[221]Chandra KP, Shiwalkar A, Kotecha J, et al. Phase I clinical studies of the advanced glycation end-product (AGE)-breaker TRC4186:safety, tolerability and pharmacokinetics in healthy subjects. Clin Drug Investig\,2009; 29(9):559-575.
[222]Schmidt AM, Hori O, Cao R, et al. RAGE:a novel cellular receptor for advanced glycation end products. Diabetes,1996; 45(suppl 3):S77-80.
[223]Penfold SA, Coughlan MT, Patel SK, et al. Circulating high-molecular-weight RAGE ligands activate pathways implicated in the development of diabetic nephropathy. Kidney Int,2010; 78(3):287-95.
[224]Katakami N, Matsuhisa M, Kaneto H, et al. Decreased endogenous secretory advanced glycation end product receptor in type 1 diabetic patients:its possible association with diabetic vascular complications. Diabetes Care,2005; 28(11):2716-2821.
[225]Jensen LJ, Denner L, Schrijvers BF, et al. Renal effects of a neutralising RAGE antibody in long-term streptozotocin-diabetic mice. J Endocrinol,2006; 188(3):493-501.
[226]Maeda S, Matsui T, Takeuchi M, et al. Pigment epithelium-derived factor (PEDF) inhibits proximal tubular cell injury in early diabetic nephropathy by suppressing advanced glycation end products (AGEs)-receptor (RAGE) axis. Pharmacol Res,2011; 63(3):241-248.
[227]Sourris KC, Forbes JM. Interactions between advanced glycation end-products (AGE) and their receptors in the development and progression of diabetic nephropathy-are these receptors valid therapeutic targets. Curr Drug Targets 2009; 10(1):42-50.
[228]Sharma K, Jin Y, Guo J, et al. Neutralization of TGF-beta by anti-TGF-beta antibody attenuates kidney hypertrophy and the enhanced extracellular matrix gene expression in STZ-induced diabetic mice. Diabetes,1996; 45(4):522-530.
[229]Ziyadeh FN, Hoffman BB, Han DC, et al. Long-term prevention of renal insufficiency, excess matrix gene expression, and glomerular mesangial matrix expansion by treatment with monoclonal antitransforming growth factor-beta antibody in db/db diabetic mice. Proc Natl Acad Sci U S A.2000; 97(14):8015-8020.
[230]Benigni A, Zoja C, Campana M, et al. Beneficial effect of TGFbeta antagonism in treating diabetic nephropathy depends on when treatment is started. Nephron Exp Nephrol,2006; 104(4):e158-68.
[231]Hill C, Flyvbjerg A, Rasch R, et al. Transforming growth factor-beta2 antibody attenuates fibrosis in the experimental diabetic rat kidney. J Endocrinol, 2001;170(3):647-651.
[232]Flyvbjerg A, Khatir D, Jensen LJN, et al. Long-term renal effects of a neutralizing CTGF-antibody in obese type 2 diabetic mice [Abstract]. J Am Soc Nephrol,2004; 15:261 A.
[233]Adler SG, Schwartz S, Williams ME, et al. Phase 1 study of anti-CTGF monoclonal antibody in patients with diabetes and microalbuminuria. Clin J Am Soc Nephrol,2010; 5(8):1420-1428.
[234]de Vriese AS, Tilton RG, Elger M, et al. Antibodies against vascular endothelial growth factor improve early renal dysfunction in experimental diabetes. J Am Soc Nephrol,2001; 12(5):993-1000.
[235]Flyvbjerg A, Dagnaes-Hansen F, De Vriese AS, et al. Amelioration of long-term renal changes in obese type 2 diabetic mice by a neutralizing vascular endothelial growth factor antibody. Diabetes,2002; 51(10):3090-3094.
[236]Schrijvers BF, Flyvbjerg A, Tilton RG, et al. A neutralizing VEGF antibody prevents glomerular hypertrophy in a model of obese type 2 diabetes, the Zucker diabetic fatty rat. Nephrol Dial Transplant,2006; 21(2):324-329.
[237]Schrijvers BF, De Vriese AS, Tilton RG, et al. Inhibition of vascular endothelial growth factor (VEGF) does not affect early renal changes in a rat model of lean type 2 diabetes. Horm Metab Res,2005; 37(1):21-25.
[238]Boor P, Floege J. Chronic kidney disease growth factors in renal fibrosis. Clin Exp Pharmacol Physiol,2011; 38(7):391-400.
[239]Hui L, Hong Y, Jingjing Z, et al. HGF suppresses high glucose-mediated oxidative stress in mesangial cells by activation of PKG and inhibition of PKA. Free Radic Biol Med,2010; 49(3):467-73.
[240]Mizuno S, Nakamura T. Suppressions of chronic glomerular injuries and TGF-beta 1 production by HGF in attenuation of murine diabetic nephropathy. Am J Physiol Renal Physiol,2004; 286(1):F134-143.
[241]Mou S, Wang Q, Shi B, et al. Hepatocyte growth factor ameliorates progression of interstitial injuries in tubular epithelial cells. Scand J Urol Nephrol,2010; 44(2):121-128.
[242]Yang J, Liu Y. Blockage of tubular epithelial to myofibroblast transition by hepatocyte growth factor prevents renal interstitial fibrosis. J Am Soc Nephrol, 2002; 13(1):96-107.
[243]Mou S, Wang Q, Shi B, et al. Hepatocyte growth factor suppresses transforming growth factor-beta-1 and type III collagen in human primary renal fibroblasts. Kaohsiung J Med Sci,2009; 25(11):577-587.
[244]Kagawa T, Takemura G, Kosai K, et al. Hepatocyte growth factor gene therapy slows down the progression of diabetic nephropathy in db/db mice. Nephron Physiol,2006; 102(3-4):p92-102.
[245]Dai C, Yang J, Bastacky S, et al. Intravenous administration of hepatocyte growth factor gene ameliorates diabetic nephropathy in mice. J Am Soc Nephrol,2004; 15(10):2637-2647.
[246]Cruzado JM, Lloberas N, Torras J, et al. Regression of advanced diabetic nephropathy by hepatocyte growth factor gene therapy in rats. Diabetes,2004; 53(4):1119-1127.
[247]Zeisberg M, Hanai J, Sugimoto H, et al. BMP-7 counteracts TGF-betal-induced epithelial-to-mesenchymal transition and reverses chronic renal injury. Nat Med,2003; 9(7):964-968.
[248]Zeisberg M, Shah AA, Kalluri R. Bone morphogenic protein-7 induces mesenchymal to epithelial transition in adult renal fibroblasts and facilitates regeneration of injured kidney. J Biol Chem,2005; 280(9):8094-8100.
[249]Xu Y, Wan J, Jiang D, et al. BMP-7 counteracts TGF-betal-induced epithelial-to-mesenchymal transition in human renal proximal tubular epithelial cells. J Nephrol,2009; 22(3):403-410.
[250]Dudas PL, Argentieri RL, Farrell FX. BMP-7 fails to attenuate TGF-betal-induced epithelial-to-mesenchymal transition in human proximal tubule epithelial cells. Nephrol Dial Transplant,2009; 24(5):1406-1416.
[251]Wang S, Hirschberg R. BMP7 antagonizes TGF-beta-dependent fibrogenesis in mesangial cells. Am J Physiol Renal Physiol,2003; 284(5):F1006-1013.
[252]Sugimoto H, Grahovac G, Zeisberg M, et al. Renal fibrosis and glomerulosclerosis in a new mouse model of diabetic nephropathy and its regression by bone morphogenic protein-7 and advanced glycation end product inhibitors. Diabetes 2007; 56(7):1825-1833.
[253]Wang S, Chen Q, Simon TC, et al. Bone morphogenic protein-7 (BMP-7), a novel therapy for diabetic nephropathy. Kidney Int,2003; 63(6):2037-2049.
[254]Wang S, de Caestecker M, Kopp J, et al. Renal bone morphogenetic protein-7 protects against diabetic nephropathy. J Am Soc Nephrol,2006; 17(9):2504-2512.
[255]Noh H, King GL. The role of PKC activation in diabetic nephropathy. Kidney Int Suppl,2007; 106:S49-53
[256]Parker PJ, Murray-Rust J. PKC at a glance. J Cell Sci,2004; 117(Pt 2):131-132.
[257]Li J, Gobe G. PKC activation and its role in kidney disease. Nephrology,2006; 11(5):428-434.
[258]Koya D, Haneda M, Nakagawa H, et al. Amelioration of accelerated diabetic mesangial expansion by treatment with a PKC beta inhibitor in diabetic db/db mice, a rodent model for type 2 diabetes. FASEB J,2000; 14(3):439-447.
[259]Kelly DJ, Zhang Y, Hepper C, et al. Protein kinase C beta inhibition attenuates the progression of experimental diabetic nephropathy in the presence of continued hypertension. Diabetes,2003; 52(2):512-518.
[260]Tuttle KR, Bakris GL, Toto RD, et al. The effect of ruboxistaurin on nephropathy in type 2 diabetes. Diabetes Care.2005; 28(11):2686-2690.
[261]Thallas-Bonke V, Lindschau C, Rizkalla B, et al. Attenuation of extracellular matrix accumulation in diabetic nephropathy by the advanced glycation end product cross-link breaker ALT-711 via a protein kinase C-alpha-dependent pathway. Diabetes,2004; 53(11):2921-2930.
[262]Thallas-Bonke V, Thorpe SR, Coughlan MT, et al. Inhibition of NADPH oxidase prevents advanced glycation end product-mediated damage in diabetic nephropathy through a protein kinase C-a-dependent pathway. Diabetes,2008; 57(2):460-469.
[263]Godel M, Hartleben B, Herbach N, et al. Role of mTOR in podocyte function and diabetic nephropathy in humans and mice. J Clin Invest,2011; 121(6):2197-2209.
[264]Yang Y, Wang J, Qin L, et al. Rapamycin prevents early steps of the development of diabetic nephropathy in rats. Am J Nephrol,2007; 27(5):495-502.
[265]Wittmann S, Daniel C, Stief A, et al. Long-term treatment of sirolimus but not cyclosporine ameliorates diabetic nephropathy in rats. Transplantation,2009; 87(9):1290-1299.
[266]Sakaguchi M, Isono M, Isshiki K, et al. Inhibition of mTOR signaling with rapamycin attenuates renal hypertrophy in the early diabetic mice. Biochem Biophys Res Commun,2006; 340(1):296-301.
[267]Mori H, Inoki K, Masutani K, et al. The mTOR pathway is highly activated in diabetic nephropathy and rapamycin has a strong therapeutic potential. Biochem Biophys Res Commun,2009; 384(4):471-475.
[268]Cheng L, Chen J, Mao X. Everolimus vs. rapamycin for treating diabetic nephropathy in diabetic mouse model. J Huazhong Univ Sci Technolog Med Sci,2011;31(4):457-462.
[269]Navarro-Gonzalez JF, Mora-Fernandez C, et al. Inflammatory molecules and pathways in the pathogenesis of diabetic nephropathy. Nat Rev Nephrol,2011; 7(6):327-340.
[270]Tamada S, Nakatani T, Asai T, et al. Inhibition of nuclear factor-kappaB activation by pyrrolidine dithiocarbamate prevents chronic FK506 nephropathy. Kidney Int,2003; 63(1):306-314.
[271]Fujihara CK, Antunes GR, Mattar AL, et al. Chronic inhibition of nuclear factor-kappaB attenuates renal injury in the 5/6 renal ablation model. Am J Physiol Renal Physiol,2007; 292(1):F92-99.
[272]Tapia E, Sanchez-Gonzalez DJ, Medina-Campos ON, et al. Treatment with pyrrolidine dithiocarbamate improves proteinuria, oxidative stress, and glomerular hypertension in overload proteinuria. Am J Physiol Renal Physiol, 2008;295(5):F1431-1439.
[273]Malaguarnera L, Pilastro MR, DiMarco R, et al. Cell death in human acute myelogenous leukemic cells induced by pyrrolidinedithiocarbamate. Apoptosis, 2003; 8(5):539-545.
[274]Morais C, Gobe G, Johnson DW, et al. Anti-angiogenic actions of pyrrolidine dithiocarbamate, a nuclear factor kappa B inhibitor. Angiogenesis,2009; 12(4):365-379.
[275]Deb DK, Chen Y, Zhang Z, et al.1,25-Dihydroxyvitamin D3 suppresses high glucose-induced angiotensinogen expression in kidney cells by blocking the NF-{kappa}B pathway. Am J Physiol Renal Physiol.2009; 296(5):F1212-218.
[276]Liu W, Zhang X, Liu P, et al. Effects of berberine on matrix accumulation and NF-kappa B signal pathway in alloxan-induced diabetic mice with renal injury. Eur J Pharmacol,2010; 638(1-3):150-155.
[277]Seaquist ER, Goetz FC, Rich S, et al. Familial clustering of diabetic kidney disease. Evidence for genetic susceptibility to diabetic nephropathy. N Engl J Med,1989; 320(18):1161-1165.
[278]Conway BR, Maxwell AP. Genetics of diabetic nephropathy:are there clues to the understanding of common kidney diseases? Nephron Clin Pract,2009; 112(4):c213-221.
[279]Susztak K, Sharma K, Schiffer M, et al. Genomic strategies for diabetic nephropathy. J Am Soc Nephrol,2003; 14(8 Suppl 3):S271-278.
[280]Smith MP, Banks RE, Wood SL, et al. Application of proteomic analysis to the study of renal diseases. Nat Rev Nephrol,2009; 5(12):701-712.