大黄酸对肥胖糖尿病大鼠肾脏保护作用及其机制探讨
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摘要
第一部分大黄酸对肥胖糖尿病大鼠的肾脏保护作用
背景与目的
糖尿病肾病(diabetic nephropathy,DN )是糖尿病(diabetes mellitus, DM)常见的慢性并发症之一,在糖尿病患者中20–40%会发生DN,在欧美,DN是引发终末期肾病(end stage renal disease,ESRD)的首要原因。其发病机制虽未完全阐明,但糖代谢紊乱引起多元醇通路、蛋白激酶C、晚期糖基化产物、己糖胺4种途径的激活、肾脏血流动力学改变、氧化应激、多种细胞因子以及遗传背景均起重要作用。近年研究认为,氧化应激在DN的发生、发展中起着重要作用,是DM微血管和大血管并发症病变发生的共同病理生理通路。中药大黄及其复方制剂在控制DN症状及延缓病情发展方面显示了很好的疗效,大黄酸(4,5dihydroxyanthraquinone-2-carboxylicacid,Rhein)为大黄的有效成分,在治疗DN的研究中已有一定的进展。研究资料显示,大黄酸除改善糖脂代谢外,有减少尿白蛋白排泄量,预防血肌酐水平的升高,改善肾小球肥大、基质增生,使肾组织转化生长因子β(transforming growth factor-β,TGF-β)以及纤维粘连蛋白(fibronectin,FN)等在肾脏的表达下调,抑制肾间质成纤维细胞的增殖等作用。但大黄酸是否具有抗氧化作用迄今未见报道。本实验旨在进一步验证大黄酸对肥胖糖尿病大鼠糖脂代谢、尿蛋白排泄的影响,并观察其对大鼠肾脏氧化应激的作用,揭示大黄酸防治DN的机制。
方法
肥胖糖尿病大鼠用高糖高脂饮食加链脲佐菌素(Streptozotocin,STZ)诱导,造模大鼠予高糖高脂饲料喂养8周后单次腹腔内注射2% STZ 25mg/kg,72小时后,取尾静脉血用快速血糖仪测定血糖,血糖﹥16.7 mmol/L,体重>395g者列入观察对象。将大鼠随机分5组,雷米普利组(DM-RA)予雷米普利1mg·kg-1·d-1灌胃;大黄酸组(DM-RH)予大黄酸100mg·kg-1·d-1灌胃;吡格列酮组(DM-PI)予盐酸吡格列酮10mg·kg-1·d-1灌胃;正常对照组(NC)和糖尿病模型组(DM)予生理盐水10ml·kg-1·d-1灌胃。各组大鼠均每天给药一次至实验结束,8周时留取24小时尿液测定24 h尿蛋白定量,用20%乌拉坦溶液腹腔内注射麻醉大鼠,留取血标本及肾组织,检测血糖、血脂、肾皮质超氧化物歧化酶(superoxide dismutase,SOD)活性和丙二醛(malondialdehyde, MDA)含量等的变化。
结果
采用高糖高脂加STZ饮食诱导的糖尿病大鼠血糖、体重、总胆固醇(cholesterol,CHOL)、甘油三酯(triglyceride,TG)、低密度脂蛋白胆固醇(low density lipoprotein cholesterol ,LDL-C)、24小时尿蛋白定量均明显高于正常对照组(P <0.01),治疗8周后大黄酸组、吡格列酮组血糖低于糖尿病模型组(P <0.01),且比治疗前明显下降(P <0.01),说明大黄酸与吡格列酮均有一定的控制血糖作用;大黄酸组与治疗前比较体重明显下降(P <0.05), CHOL、TG、LDL低于糖尿病模型组(P <0.01);大黄酸组、雷米普利组、吡格列酮组24 h尿蛋白量均显著低于糖尿病模型组(P <0.01);与正常对照组比较,糖尿病大鼠MDA含量明显增加,SOD活性明显降低(P <0.01);大黄酸治疗后肾组织MDA含量明显降低,SOD活性明显增加(P <0.05)。
结论
大黄酸具有改善糖脂代谢异常,减少尿蛋白排泄、抗氧化应激的作用,这可能是其预防和延缓DN进程的机制之一。
第二部分大黄酸对肥胖糖尿病大鼠肾皮质过氧化物酶体增殖体激活受体γ表达的影响
背景与目的
过氧化物酶体增殖体激活受体(peroxisome proliferators activated-receptors, PPARs)是一类配体依赖性转录因子,属于核受体超家族成员,是调节脂肪活化因子转录、脂质代谢、炎症反应、细胞增殖和分化的重要因子,PPARs有三种亚型,即PPARα、PPARβ/δ和PPARγ,PPARγ及其配体在DN发病和治疗中的作用日益受到重视。大量的实验研究表明,激活PPARγ能减少蛋白尿及减轻肾组织的损伤,显著抑制系膜细胞的增殖反应、细胞外基质(extra cellular matrix, ECM)的分泌表达以及多种炎性细胞因子的分泌。临床研究也证明应用PPARγ激动剂可明显降低糖尿病患者尿白蛋白的排出,使尿白蛋白/肌酐比值(ACR)显著下降; TGF-β是DN复杂的细胞因子网络中的核心因子,是肾脏损伤的关键致病因子。具有促使肾脏固有细胞肥大、刺激ECM分子合成的作用,在DN发病机制的各个环节起着重要作用。有研究表明,激活PPARγ可下调TGF-β1、FN、Ⅳ型胶原、纤溶酶原激活物抑制因子-1的表达,达到肾脏保护作用。DM时肾脏PPARγ的表达报道不一,且大黄酸对肾脏PPARγ表达的影响也未有报道。本实验通过观察肥胖糖尿病大鼠肾脏PPARγ的mRNA和蛋白表达,以及TGF-β1的mRNA表达及大黄酸对二者表达的影响,试图进一步揭示大黄酸防治DN的机制。
方法
造模、分组、给药、处死方法等同第一部分实验,取血完毕后,经生理盐水反复灌洗至肾脏转为苍白色,迅速取肾,保存于-70℃冰箱中。采用免疫组化(immunohistochemistry,ICH)、逆转录聚合酶链式反应(reverse transcription-polymerase chain reaction,RT-PCR)、蛋白印迹(western blotting)等方法,观察各组大鼠肾皮质PPARγ基因与蛋白表达和TGF—β1基因表达的影响。
结果
正常对照组大鼠肾皮质中PPARγmRNA有一定的基础表达,高糖高脂加STZ诱导的糖尿病大鼠肾皮质中PPARγmRNA表达和蛋白表达与正常对照组相比明显增加(P <0.01),经大黄酸和吡格列酮治疗8周后,PPARγ的表达量进一步升高(P <0.05,P <0.01)。免疫组化结果与RT-PCR和Western blotting结果相似。正常对照组大鼠肾皮质TGF-β1呈低水平表达,糖尿病模型组大鼠TGF-β1呈高表达(P <0.01),而大黄酸组、雷米普利组、吡格列酮组TGF-β1表达水平均低于糖尿病模型组(P <0.01)。
结论
肥胖糖尿病大鼠肾皮质PPARγ和TGF-β1的表达增加,大黄酸治疗可明显提高PPARγ的表达,下调TGF-β1的表达,大黄酸通过激活PPARγ从而下调TGF—β1可能是大黄酸防治DN的另一机制。
PARTⅠ: To investigate the protective effect of Rhein on kidneys in obese diabetic rats.
Background and objective Diabetic nephropathy(DN) is one of the most common complications of diabetes mellitus(DM), its incidence in DM is 20–40%.It is the leading cause of end-stage renal disease in the west world. The pathophysiological mechanism responsible for DN has not been fully understood yet. There are some important factors such as renal polyalcohol pathway, advanced glycation end products(AGEs), activation of Protein Kinase C,oxidative stress, hexosamine , renal hemodynamic change , many kinds of cytokines and genetic background and so on. Recent studies show that oxidative stress plays a role in the occurrence and development, it was the common physiological and pathological pathway of the diabetic complication of the great vessels and micrangium. Rhubarb and its compound preparation are effective on controlling the symptom of DN and delaying the progress of disease. Rhein as the effective ingredient of Rhubarb has major progress in the research of the treatment of DN. Reseach data demonstrates that Rhein can reduce the urinary albumin, prevent the elevation of SCr, relieve the glomerular sclerosis and improve the glucolipid metabolism. But up to now there is no report whether Rhein has antioxidant function. This experiment aims to confirm the effect of Rhein on glucolipid metabolism and urinary albumin excretion in Obese Diabetic Rats, to observe antioxidation of Rhein on renal, and to investigate the possible mechanism of Rhein preventing and delaying diabetic nephrophy.
Methods Male Wistar rats were fed with the diets enriched with sucrose (20%) and lard (10%) and cholesterol (2.5%) and cholic acid (1%).Hyperglycemia was developed by intraperitoneal injection in these rats with 25 mg/kg streptozotocin (STZ) after 8 weeks on the diets.All rats were devided into 5 groups randomly: normal control group (NC),diabetic group(DM), diabetic rats receiving Rhein(DM-RH), diabetic rats receiving Ramipril(DM-RA) and diabetic rats receiving pioglitazone(DM-PI). After administration by gavage for 8 weeks,blood glucose, body weight, blood fat, 24h urinary protein excretion,the content of malondialdehyde (MDA) and superoxide dismutase(SOD) of the cortex renis were measured.
Results After modeling the following indexes including blood glucose, body weight, Cholesterol(CHOL),Triglyceride(TG),High density lipoprotein-cholesterol (HDL-C),Low density Lipoprotein Cholesterol (LDL-C) and 24h urinary protein excretion were increased distinctly. After 8 weeks, compared with DM, the glucose of DM-RH and DM-PI was decreased markedly(P < 0.01), the glucose was decreased obviously after the treatment(P <0.01), and the group comparison was no significant difference(P >0.05);CHOL,TG,LDL of DM+RH was lower than DM(P <0.01), but DM-RA and DM-PI not(P >0.05); The 24h urinary protein excretion of DM-RA, DM-PI and DM-RH was obviously lower than DM(P <0.01), DM-RA was superior to DM-PI(P <0.05),but the group comparison between DM-RA and DM-RH was no significant difference(P >0.05).Compared with NC, the level of MDA of DM,DM-RA, DM-PI and DM-RH was increased significantly(P <0.01), the activity of T-SOD was decreased(P <0.01). After the treatment, The level of MDA of DM-RA, DM-PI and DM-RH was increased significantly(P <0.05), the activity of T-SOD was decreased(P <0.05,P <0.01).
Conclusion Rhein can control glucose, adjust blood fat, reduce the urinary protein excretion. The antioxidation may be one of the possible mechanisms that Rhein can protect and remitte diabetic nephropathy.
PARTⅡ: To investigate the effect of Rhein on the expression of peroxisome proliferators-activated receptors-γ(PPARγ) and transforming growth factor-β1 (TGF-β1) in the cortex renis of the obese diabetic rats.
Background and objective Peroxisome proliferators-activated receptors (PPARs) are member of the nuclear receptor superfamily of ligands-dependent transcription factors. These receptors are important to regulate lipid-activated gene transcription, lipid metabolism, inflammation and cell proliferation and differentiation of the cells. and its ligand have been attracted enormous attention due to the key role these receptors play in treatment of DN. Growing laboratorial evidence points to activated PPARγcan reduce the urinary protein and the injury of the nephridial tissue, and inhibit the proliferation of the mesangial cells, the expression of extracellularmatrix secretion and secretion of the inflammatory cytokines. Clinical research demonstrates that PPARγactivator can reduce obviously diabetic urinary protein excretion, urinary protein excretion/creatinine(ACR). TGF-β1 is the kernel factor of the complicate DN cytokine network, and pivotal causative agent due to the renal injury. TGF-β1 has important effects in the pathogenesis of DN such as inducing the proliferation and hypertrophy of the renal cells and stimulating the molecular synthesizing of the ECM. Some research show that activated PPARγcan protect kidney due to reducing the genic expression of TGF-β1, plasminogen activator inhibitor-1 (PAI-1), fibronectin(FN) and typeⅣcollagen. There are different reports about the expression of PPARγin diabetic nephropathy. And there is no report about the effect of Rhein on the PPARγexpression of kidney. In this experiment, we observe the expression of PPARγand TGF-β1 in the cortex renis of the obese diabetic rats, and the effect of Rhein , to reveal the multiplicitas mechanisms that Rhein can protect and remitte diabetic nephropathy.
Methods The methods of modeling, diving group, administration, and so on are the same to Part I. We observed that the effect of the Rhein on the expression of PPARγand TGF-β1 in the cortex renis of the obese diabetic rats induced by streptozotocin , high glucos and fat diet with the method of immune histochemistry, RT-PCR and western blot, and investigate the multiple mechanism of the prevention to DN of the Rhein.
Results Compared with normal control group, the expression of PPARγin the rats of diabetic group(DM), diabetic rats receiving Rhein(DM-RH) and diabetic rats receiving pioglitazone(DM-PI) were increased markedly(P <0.01,P <0.05).The expression of PPARγin the rats of DM receiving Rhein(DM-RH) and diabetic rats receiving pioglitazone(DM-PI) were increased markedly than those in the rats of diabetic group(DM)(P <0.01,P <0.05).There was no significant difference between DM and diabetic rats receiving Ramipril(DM-RA) (P >0.05). The expression of TGF-β1mRNA of the cortex renis in diabetic group(DM) was increased than those in normal control group(NC)(P <0.01).The expression of TGF-β1mRNA of the cortex renis in diabetic group(DM) was decresed markedly than those in DM+RH, DM+RA and DM+PI(P <0.05).
Conclusion Rhein can increase the mRNA and protein expression of PPARγ, and reduce the expression of TGF-β1, Rhein can activate PPARγand reduce the function of TGF-β1. It may be another possible mechanism that Rhein can protect and remitte diabetic nephropathy.
背景与目的
糖尿病肾病(diabetic nephropathy,DN )是糖尿病(diabetes mellitus, DM)常见的慢性并发症之一,在糖尿病患者中20–40%会发生DN,在欧美,DN是引发终末期肾病(end stage renal disease,ESRD)的首要原因。其发病机制虽未完全阐明,但糖代谢紊乱引起多元醇通路、蛋白激酶C、晚期糖基化产物、己糖胺4种途径的激活、肾脏血流动力学改变、氧化应激、多种细胞因子以及遗传背景均起重要作用。近年研究认为,氧化应激在DN的发生、发展中起着重要作用,是DM微血管和大血管并发症病变发生的共同病理生理通路。中药大黄及其复方制剂在控制DN症状及延缓病情发展方面显示了很好的疗效,大黄酸(4,5dihydroxyanthraquinone-2-carboxylicacid,Rhein)为大黄的有效成分,在治疗DN的研究中已有一定的进展。研究资料显示,大黄酸除改善糖脂代谢外,有减少尿白蛋白排泄量,预防血肌酐水平的升高,改善肾小球肥大、基质增生,使肾组织转化生长因子β(transforming growth factor-β,TGF-β)以及纤维粘连蛋白(fibronectin,FN)等在肾脏的表达下调,抑制肾间质成纤维细胞的增殖等作用。但大黄酸是否具有抗氧化作用迄今未见报道。本实验旨在进一步验证大黄酸对肥胖糖尿病大鼠糖脂代谢、尿蛋白排泄的影响,并观察其对大鼠肾脏氧化应激的作用,揭示大黄酸防治DN的机制。
方法
肥胖糖尿病大鼠用高糖高脂饮食加链脲佐菌素(Streptozotocin,STZ)诱导,造模大鼠予高糖高脂饲料喂养8周后单次腹腔内注射2% STZ 25mg/kg,72小时后,取尾静脉血用快速血糖仪测定血糖,血糖﹥16.7 mmol/L,体重>395g者列入观察对象。将大鼠随机分5组,雷米普利组(DM-RA)予雷米普利1mg·kg-1·d-1灌胃;大黄酸组(DM-RH)予大黄酸100mg·kg-1·d-1灌胃;吡格列酮组(DM-PI)予盐酸吡格列酮10mg·kg-1·d-1灌胃;正常对照组(NC)和糖尿病模型组(DM)予生理盐水10ml·kg-1·d-1灌胃。各组大鼠均每天给药一次至实验结束,8周时留取24小时尿液测定24 h尿蛋白定量,用20%乌拉坦溶液腹腔内注射麻醉大鼠,留取血标本及肾组织,检测血糖、血脂、肾皮质超氧化物歧化酶(superoxide dismutase,SOD)活性和丙二醛(malondialdehyde, MDA)含量等的变化。
结果
采用高糖高脂加STZ饮食诱导的糖尿病大鼠血糖、体重、总胆固醇(cholesterol,CHOL)、甘油三酯(triglyceride,TG)、低密度脂蛋白胆固醇(low density lipoprotein cholesterol ,LDL-C)、24小时尿蛋白定量均明显高于正常对照组(P <0.01),治疗8周后大黄酸组、吡格列酮组血糖低于糖尿病模型组(P <0.01),且比治疗前明显下降(P <0.01),说明大黄酸与吡格列酮均有一定的控制血糖作用;大黄酸组与治疗前比较体重明显下降(P <0.05), CHOL、TG、LDL低于糖尿病模型组(P <0.01);大黄酸组、雷米普利组、吡格列酮组24 h尿蛋白量均显著低于糖尿病模型组(P <0.01);与正常对照组比较,糖尿病大鼠MDA含量明显增加,SOD活性明显降低(P <0.01);大黄酸治疗后肾组织MDA含量明显降低,SOD活性明显增加(P <0.05)。
结论
大黄酸具有改善糖脂代谢异常,减少尿蛋白排泄、抗氧化应激的作用,这可能是其预防和延缓DN进程的机制之一。
第二部分大黄酸对肥胖糖尿病大鼠肾皮质过氧化物酶体增殖体激活受体γ表达的影响
背景与目的
过氧化物酶体增殖体激活受体(peroxisome proliferators activated-receptors, PPARs)是一类配体依赖性转录因子,属于核受体超家族成员,是调节脂肪活化因子转录、脂质代谢、炎症反应、细胞增殖和分化的重要因子,PPARs有三种亚型,即PPARα、PPARβ/δ和PPARγ,PPARγ及其配体在DN发病和治疗中的作用日益受到重视。大量的实验研究表明,激活PPARγ能减少蛋白尿及减轻肾组织的损伤,显著抑制系膜细胞的增殖反应、细胞外基质(extra cellular matrix, ECM)的分泌表达以及多种炎性细胞因子的分泌。临床研究也证明应用PPARγ激动剂可明显降低糖尿病患者尿白蛋白的排出,使尿白蛋白/肌酐比值(ACR)显著下降; TGF-β是DN复杂的细胞因子网络中的核心因子,是肾脏损伤的关键致病因子。具有促使肾脏固有细胞肥大、刺激ECM分子合成的作用,在DN发病机制的各个环节起着重要作用。有研究表明,激活PPARγ可下调TGF-β1、FN、Ⅳ型胶原、纤溶酶原激活物抑制因子-1的表达,达到肾脏保护作用。DM时肾脏PPARγ的表达报道不一,且大黄酸对肾脏PPARγ表达的影响也未有报道。本实验通过观察肥胖糖尿病大鼠肾脏PPARγ的mRNA和蛋白表达,以及TGF-β1的mRNA表达及大黄酸对二者表达的影响,试图进一步揭示大黄酸防治DN的机制。
方法
造模、分组、给药、处死方法等同第一部分实验,取血完毕后,经生理盐水反复灌洗至肾脏转为苍白色,迅速取肾,保存于-70℃冰箱中。采用免疫组化(immunohistochemistry,ICH)、逆转录聚合酶链式反应(reverse transcription-polymerase chain reaction,RT-PCR)、蛋白印迹(western blotting)等方法,观察各组大鼠肾皮质PPARγ基因与蛋白表达和TGF—β1基因表达的影响。
结果
正常对照组大鼠肾皮质中PPARγmRNA有一定的基础表达,高糖高脂加STZ诱导的糖尿病大鼠肾皮质中PPARγmRNA表达和蛋白表达与正常对照组相比明显增加(P <0.01),经大黄酸和吡格列酮治疗8周后,PPARγ的表达量进一步升高(P <0.05,P <0.01)。免疫组化结果与RT-PCR和Western blotting结果相似。正常对照组大鼠肾皮质TGF-β1呈低水平表达,糖尿病模型组大鼠TGF-β1呈高表达(P <0.01),而大黄酸组、雷米普利组、吡格列酮组TGF-β1表达水平均低于糖尿病模型组(P <0.01)。
结论
肥胖糖尿病大鼠肾皮质PPARγ和TGF-β1的表达增加,大黄酸治疗可明显提高PPARγ的表达,下调TGF-β1的表达,大黄酸通过激活PPARγ从而下调TGF—β1可能是大黄酸防治DN的另一机制。
PARTⅠ: To investigate the protective effect of Rhein on kidneys in obese diabetic rats.
Background and objective Diabetic nephropathy(DN) is one of the most common complications of diabetes mellitus(DM), its incidence in DM is 20–40%.It is the leading cause of end-stage renal disease in the west world. The pathophysiological mechanism responsible for DN has not been fully understood yet. There are some important factors such as renal polyalcohol pathway, advanced glycation end products(AGEs), activation of Protein Kinase C,oxidative stress, hexosamine , renal hemodynamic change , many kinds of cytokines and genetic background and so on. Recent studies show that oxidative stress plays a role in the occurrence and development, it was the common physiological and pathological pathway of the diabetic complication of the great vessels and micrangium. Rhubarb and its compound preparation are effective on controlling the symptom of DN and delaying the progress of disease. Rhein as the effective ingredient of Rhubarb has major progress in the research of the treatment of DN. Reseach data demonstrates that Rhein can reduce the urinary albumin, prevent the elevation of SCr, relieve the glomerular sclerosis and improve the glucolipid metabolism. But up to now there is no report whether Rhein has antioxidant function. This experiment aims to confirm the effect of Rhein on glucolipid metabolism and urinary albumin excretion in Obese Diabetic Rats, to observe antioxidation of Rhein on renal, and to investigate the possible mechanism of Rhein preventing and delaying diabetic nephrophy.
Methods Male Wistar rats were fed with the diets enriched with sucrose (20%) and lard (10%) and cholesterol (2.5%) and cholic acid (1%).Hyperglycemia was developed by intraperitoneal injection in these rats with 25 mg/kg streptozotocin (STZ) after 8 weeks on the diets.All rats were devided into 5 groups randomly: normal control group (NC),diabetic group(DM), diabetic rats receiving Rhein(DM-RH), diabetic rats receiving Ramipril(DM-RA) and diabetic rats receiving pioglitazone(DM-PI). After administration by gavage for 8 weeks,blood glucose, body weight, blood fat, 24h urinary protein excretion,the content of malondialdehyde (MDA) and superoxide dismutase(SOD) of the cortex renis were measured.
Results After modeling the following indexes including blood glucose, body weight, Cholesterol(CHOL),Triglyceride(TG),High density lipoprotein-cholesterol (HDL-C),Low density Lipoprotein Cholesterol (LDL-C) and 24h urinary protein excretion were increased distinctly. After 8 weeks, compared with DM, the glucose of DM-RH and DM-PI was decreased markedly(P < 0.01), the glucose was decreased obviously after the treatment(P <0.01), and the group comparison was no significant difference(P >0.05);CHOL,TG,LDL of DM+RH was lower than DM(P <0.01), but DM-RA and DM-PI not(P >0.05); The 24h urinary protein excretion of DM-RA, DM-PI and DM-RH was obviously lower than DM(P <0.01), DM-RA was superior to DM-PI(P <0.05),but the group comparison between DM-RA and DM-RH was no significant difference(P >0.05).Compared with NC, the level of MDA of DM,DM-RA, DM-PI and DM-RH was increased significantly(P <0.01), the activity of T-SOD was decreased(P <0.01). After the treatment, The level of MDA of DM-RA, DM-PI and DM-RH was increased significantly(P <0.05), the activity of T-SOD was decreased(P <0.05,P <0.01).
Conclusion Rhein can control glucose, adjust blood fat, reduce the urinary protein excretion. The antioxidation may be one of the possible mechanisms that Rhein can protect and remitte diabetic nephropathy.
PARTⅡ: To investigate the effect of Rhein on the expression of peroxisome proliferators-activated receptors-γ(PPARγ) and transforming growth factor-β1 (TGF-β1) in the cortex renis of the obese diabetic rats.
Background and objective Peroxisome proliferators-activated receptors (PPARs) are member of the nuclear receptor superfamily of ligands-dependent transcription factors. These receptors are important to regulate lipid-activated gene transcription, lipid metabolism, inflammation and cell proliferation and differentiation of the cells. and its ligand have been attracted enormous attention due to the key role these receptors play in treatment of DN. Growing laboratorial evidence points to activated PPARγcan reduce the urinary protein and the injury of the nephridial tissue, and inhibit the proliferation of the mesangial cells, the expression of extracellularmatrix secretion and secretion of the inflammatory cytokines. Clinical research demonstrates that PPARγactivator can reduce obviously diabetic urinary protein excretion, urinary protein excretion/creatinine(ACR). TGF-β1 is the kernel factor of the complicate DN cytokine network, and pivotal causative agent due to the renal injury. TGF-β1 has important effects in the pathogenesis of DN such as inducing the proliferation and hypertrophy of the renal cells and stimulating the molecular synthesizing of the ECM. Some research show that activated PPARγcan protect kidney due to reducing the genic expression of TGF-β1, plasminogen activator inhibitor-1 (PAI-1), fibronectin(FN) and typeⅣcollagen. There are different reports about the expression of PPARγin diabetic nephropathy. And there is no report about the effect of Rhein on the PPARγexpression of kidney. In this experiment, we observe the expression of PPARγand TGF-β1 in the cortex renis of the obese diabetic rats, and the effect of Rhein , to reveal the multiplicitas mechanisms that Rhein can protect and remitte diabetic nephropathy.
Methods The methods of modeling, diving group, administration, and so on are the same to Part I. We observed that the effect of the Rhein on the expression of PPARγand TGF-β1 in the cortex renis of the obese diabetic rats induced by streptozotocin , high glucos and fat diet with the method of immune histochemistry, RT-PCR and western blot, and investigate the multiple mechanism of the prevention to DN of the Rhein.
Results Compared with normal control group, the expression of PPARγin the rats of diabetic group(DM), diabetic rats receiving Rhein(DM-RH) and diabetic rats receiving pioglitazone(DM-PI) were increased markedly(P <0.01,P <0.05).The expression of PPARγin the rats of DM receiving Rhein(DM-RH) and diabetic rats receiving pioglitazone(DM-PI) were increased markedly than those in the rats of diabetic group(DM)(P <0.01,P <0.05).There was no significant difference between DM and diabetic rats receiving Ramipril(DM-RA) (P >0.05). The expression of TGF-β1mRNA of the cortex renis in diabetic group(DM) was increased than those in normal control group(NC)(P <0.01).The expression of TGF-β1mRNA of the cortex renis in diabetic group(DM) was decresed markedly than those in DM+RH, DM+RA and DM+PI(P <0.05).
Conclusion Rhein can increase the mRNA and protein expression of PPARγ, and reduce the expression of TGF-β1, Rhein can activate PPARγand reduce the function of TGF-β1. It may be another possible mechanism that Rhein can protect and remitte diabetic nephropathy.
引文
1 Zimmet P, Shaw J, Murray S ,et al. The diabetes epidemic in full flight: forecasting the future[J]. Diabetes Voice, 2003, 48(Special Issu): 12-16.
2国家“九五”攻关计划糖尿病研究协作组.中国12个地区中老年人糖尿病患病率调查[J].中华内分泌代谢杂志,2002,18(4):280-284.
3 American Diabetes Association:Standards of medical care in diabetes-2007[J]. Diabetes Care, 2007, 30(suppl 1),S19- S21.
4Sasso FC, Nicola LD, Carbonara O, et al.Cardiovascular risk factors and disease management in type 2 diabetic patients with diabetic nephropathy[J]. Diabetes Care, 2006,29(3):498-503.
5 American Diabetes Association.Diabetic nephropathy[J].Diabetes Care, 2003,26(Suppl 1): S94-S98.
6刘志红.糖尿病肾病的治疗[J].中国实用内科杂志,2006,26(5):322-323.
7 Palmer AJ, Tucker DD, Valentine WJ, et al. Cost-effectiveness of irbesartan in diabetic nephropathy: a systematic review of published studies[J].Nephrology Dialysis Transplantation,2005,20(6):1103-1109.
8 Bloomgarden ZT. Diabetic nephropathy[J]. Diabetes Care, 2005, 28(3):745-751.
9 Beisswenger PJ, Drummond KS, Nelson RG,et al.Susceptibility to diabetic nephropathy is related to dicarbonyl and oxidative stress [J].Diabetes, 2005, 54(11):3274-3281.
10 Brownlee M. Biochemistry and molecular cell biology of diabetic complications[J]. Nature, 2001,414(6865):813-820.
11贾忠辉,刘志红,郑敬民,等.大黄酸和辛伐他汀对db/db糖尿病小鼠脂代谢紊乱和肾脏保护作用的比较[J].肾脏病与透析肾移植杂志,2006,15(3):233-239.
12张学亮,郭啸华,刘志红,等.大黄酸对低剂量链脲佐菌素肥胖糖尿病大鼠糖尿病肾病的影响[J].中华内分泌代谢杂志,2005,21(6):563-565.
13郭啸华,刘志红,李恒,等.高糖高脂饮食诱导的2型糖尿病大鼠模型及其肾病特点[J].中国糖尿病杂志, 2002,10(5):290-294.
14唐宗琼.大黄及其复方治疗糖尿病肾病的研究进展[J].四川生理科学杂志2004, 26(4): 157-158.
15游德江.生大黄粉口服加黄芪注射液静滴治疗糖尿病肾病30例临床观察[J].四川中医,2002 20(7): 38.
16李建丰.加味大黄附子汤治疗糖尿病肾病30例临床报道.中国医药导报,2006,3(18):109.
17李六生,刘建社,陈建娜.缬沙坦联合大黄治疗糖尿病肾病的临床研究[J].临床肾脏病杂志,2006,6(4):160.
18徐小鹏.大黄对糖尿病肾病伴明显蛋白尿的临床疗效[J].国外医学.中医中药分册,2003,25 (6):347.
19王雪琴,赵凤春,吴润梅.大黄制剂与苯那普利联合治疗老年2型糖尿病肾病慢性肾功能不全临床观察[J].中国药物与临床,2007,7(6):478-479.
20龚伟,黎磊石,孙骅,等.大黄酸对糖尿病大鼠转化生长因子β及其受体表达的影响[J].肾脏病与透析肾移植杂志,2006,15(2):101-111.
21刘伦志,宁建平,恩施.大黄酸对糖尿病大鼠肾小管上皮细胞表型转化的影响[J].内科急危重症杂志, 2007,13(1):33-35.
22 Mogensen CE, Christensen CK, Vittinghus E.The stages in diabetic renal disease, with emphasis on the stage of incipient diabetic nephropathy[J]. Diabetes, 1983, 32 (Suppl 2):64–78.
23 Remuzzi G, Macia M, Ruggenenti P. Prevention and treatment of diabetic renal disease in type 2 diabetes: the BENEDICT study[J]. J Am Soc Nephrol,2006,17(4 Suppl 2):S90–S97.
24 American Diabetes Association. Standards of medical care in diabetes-2008[J]. Diabetes Care, 2008,31(Suppl 1):S12-S54.
25翁建平.糖尿病肾病的诊断与治疗.临床内科杂志,2005,22(3):150-153.
26 The Diabetes Control and Complications Research Group.Effect of intensive therapy on the development and progression of diabetic nephropathy in the Diabetes Control and Complications Trial[J]. Kidney Int,1995,47(6):1703–1720.
27 UK Prospective Diabetes Study (UKPDS) Group: Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34)[J]. Lancet,1998,352(9131):854–865.
28 UK Prospective Diabetes Study Group.Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes[J]. BMJ, 1998,317(7160): 703–713.
29 Bakris GL, Williams M, Dworkin L, et al. Preserving renal function in adults with hypertension and diabetes: a consensus approach: National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group[J]. Am J Kidney Dis,2000,36(3):646–661.
30 Kasiske BL, Lakatua JD, Ma JZ,et al. A meta-analysis of the effects of dietary protein restriction on the rate of decline in renal function[J]. Am J Kidney Dis,1998,31(6):954–961.
31王保法.糖尿病肾病治疗进展.国际内分泌分册,2006,33(9):393-396.
32谷立杰.糖尿病肾病药物治疗研究进展.国际泌尿系统杂志,2006,26(5):696-701.
33 Macisaac RJ, Jerums G.Albuminuric and non-albuminuric pathways to renal impairment in diabetes[J].Minerva Endocrinol, 2005, 30(3): 161-177.
34 Dominguz LJ, Sowers JR. Metabolic syndrome therapy: prevention of vascular injury by antidiabetic agents[J]. Curr Hypertens Rep, 2005, 7(2): 110-116.
35 Dominguez JH, Tang N, Xu W,et al. Studies of renal injuryⅢ: lipid induced nephropathy in typeⅡdiabetes[J]. Kidney Int, 2000,57(1): 92-99.
36 Mazzolai L, Korber M, Bouzourene K,et al. Severe hyperlipidemia causes impaired renin-angiotensin system function in apolipoprotein E deficient mice[J]. Atherosclerosis, 2005, 186(1):86-91.
37 Blanco S,Vaquero M,Gomez-Guerrero C, et al.Potential role of angiotensin- converting enzyme inhibitors and statins on early podocyte damage in a model of type
2 diabetes mellitus, obesity, and mild hypertension[J]. Am J Hypertens, 2005, 18(4 Pt1): 557-565.
38朱加明,刘志红,黄燕飞.大黄酸对db/db小鼠糖尿病肾病疗效的观察[J].肾脏病与透析肾移植杂志, 2OO2,11(1):3-10.
39黄燕飞,刘志红,陈惠萍,等.大黄酸和罗格列酮对db/db糖尿病小鼠代谢紊乱和肾脏损伤的作用比较[J].肾脏病与透析肾移植杂志, 2004,13(3) : 215–221.
40 Kitada M,Koya D,Sugimoto T,et al.Translocation of glomerular p47phox and p67phox by protein kinase C-? activation is required for oxidative stress in diabetic nephropathy[J] .Diabetes,2003,52(10): 2603-2614.
41常洁.氧化应激及其在糖尿病肾病中的作用.国际内科学杂志,2007,34(2):105-108.
42朱斌.糖尿病氧化应激的研究进展及其与糖尿病肾病的关系[J].国外医学泌尿系统分册,2OO4,24(6):818-822.
43 Li JM, Shah AM.ROS generation by nonphagocytic NADPH oxidase: potential relevance in diabetic nephropathy[J]. J Am Soc Nephrol ,2003,14 (8 Suppl 3):S221-S226.
44 Shiose A,Kuroda J,Tsuruya K,et a1.A novel superoxide-producing NAD(P)H oxidase in kidney[J].J Biol Chem,2001,276(2):1417-1423.
45 Onozato ML,Tojo A,Goto A,et a1.Oxidative stress and nitric oxide synthase in rat diabetic nephropatby:effects of ACEI and ARB[J].Kidney Int,2OO2,61(1):186-194.
46 Wu LL, Chiou CC, Chang PY, et al. Urinary 8-OHdG: a marker of oxidative stress to DNA and a risk factor for cancer, atherosclerosis and diabetics[J]. Clin Chim Acta, 2004, 339(1-2): 1-9.
47 Chabrashvili T,TojoA,Onozato ML,et a1.Expression and cellular localization of classic NADPH oxidase subunits in the spontaneously hypertensive rat kidney[J]. Hypertension,2OO2,39(2):269-74.
48Inoguchi T, Sonta T, Tsubouchi H, et al. Protein kinase C-dependent increase in reactive oxygen species (ROS) production in vascular tissues of diabetes: role of vascular NAD(P)H oxidase[J]. J Am Soc Nephrol,2003,14(8 Suppl3):S227-S232.
49 Chung SS, Ho EC, Lam KS, et al. Contribution of polyol pathway to diabetes-induced oxidative stress [J].J Am Soc Nephrol,2003,14(8 Suppl 3):S233-S236.
50 Fukami K, Ueda S, Yamagishi S, et al. AGEs activate mesangial TGF-beta-Smad signaling via an angiotensin typeⅠreceptor interaction[J]. Kidney Int, 2004, 66(6): 2137-2147.
51 Wautier MP, Chappey O, Corda S,et al. Activation of NADPH oxidase by AGE links oxidant stress to altered gene expression via RAGE[J].Am J Physiol Endocrinol Metab, 2001,280(5):E685-E694.
52 Yim MB, Yim HS, Lee C, et al. Protein glycation: creation of catalytic sites for free radical generation[J].Ann N Y Acad Sci,2001,928(4):48-53.
53 Lal MA,Brismar H,Eklof AC,et a1.Role of oxidative stress in advanced glycation end product-induced mesangial cell activation[J].Kidney Int,2002,61(6):2006-2014.
54 Ogawa S, Mori T, NakoK, et al. AngiotensinⅡtype 1 receptor blockers reduce urinary oxidative stress markers in hypertensive diabetic nephropathy[J]. Hypert- ension, 2006, 47(4): 699-705.
55 Leehey DJ, Isreb MA, Marcic S, et al.Effect of high glucose on superoxide in human mesangial cells: role of angiotensinⅡ[J].Nephron Exp Nephrol, 2005, 100(1): e46-53.
56 NagaiY, Yao L, Kobori H, et al.Temporary angiotensin II blockade at the prediabetic stage attenuates the development of renal injury in type 2 diabetic rats.J Am Soc Nephrol, 2005, 16(3): 703-711.
57 Yavuz D,Kucukkaya B,Haklar G,et a1.Effects of captopril and losartan on lipid peroxidation, protein oxidation and nitric oxide release in diabetic rat kidney[J]. Prostaglandins Leukot Essent Fatty Acids,2OO3,69(4):223-227.
58 Tsuji T, Mizushige K, Noma T,et al. Improvement of aortic wall distensibility andreduction of oxidative stress by pioglitazone in pre-diabetic stage of Otsuka Long-Evans Tokushima fatty rats[J].Cardiovasc Drugs Ther, 2002, 16(5):429-434.
59 Tao L, Liu HR, Gao E,et al. Antioxidative, antinitrative, and vasculoprotective effects of a peroxisome proliferator-activated receptor-gamma agonist in hypercholesterolemia.[J].Circulation, 2003,108(22):2805-2811.
60 Da Ros R,Assaloni R, Ceriello A. The preventive anti - oxidant action of thiazolidinediones: a new therapeutic prospect in diabetes and insulin resistance[J]. Diabet Med, 2004, 21 (11): 1249-1252.
61 Bagi Z,Koller A,Kaley GP. PPARγactivation,by reducing oxidative stress, increases NO bioavailability in coronary arterioles of mice with Type 2 diabetes[J].Am J Physiol Heart Circ Physiol, 2004, 286(2): H742-H748.
62高苹,贾汝汉.他汀类药物非依赖降脂的肾保护作用研究新进展[J].国外医学泌尿系统分册,2004,24(1): 882-901.
63 Yang T , Chen JW , Liu CP.Combination of simvastatin and cilazapril have preventive effect on diabetic nephropathy in diabetic rat and cultured mesangial cells[J]. Diabetologia, 2001, 44( supp1):A 2651.
64蒋晓红,董吉祥.他汀类药物防治糖尿病肾病的研究现状[J].中国糖尿病杂志2007,15(5):317-318.
65 Shah S,Paparello J,Danesh FR. Effects of statin therapy on the progression of chronic kidney disease[J]. Adv Chronic Kidney Dis,2005,12(2):187-195.
66 Yu HY, Inoguchi T, Nakayama M,et al.Statin attenuates high glucose-induced and angiotensinⅡ-induced MAP kinase activity through inhibition of NAD(P)H oxidase activity in cultured mesangial cells[J]. Med Chem, 2005, 1(5): 461-466.
67 Jones SP,Teshima Y,Akao M,et a1.Simvastatin attenuated oxidant-induced mitochondrial dysfunction in cardiac myocytes[J].Circ Res,2OO3,93 (8):697-699.
68邓晓明,韩崇旭,范钰,等.糖脉宁防治糖尿病血管并发症的实验研究[J].中国中医基础医学杂志,2001,7(4): 39-41.
69廖璞,王淑琴,廖雪松,等.银杏叶提取物对糖尿病大鼠肾脏保护作用的实验研究[J].中国药房,2000,11(3): 114-116.
70何兰杰,刘萍.枸杞多糖对糖尿病大鼠肾脏氧化应激的影响[J].中国医院药学杂志,2006,26 (12): 1475-1478.
71 Craven PA, Melhem MF, Phillips SL,et al. Overexpression of Cu2+/Zn2+ superoxide dismutase protects against early diabetic glomerular injury in transgenic mice[J]. Diabetes, 2001, 50(9):2114-2125.
1Escher P,Wahli W.Peroxisome proliferator-activated receptors:Insight into multiple cellular functions[J].Mut Res,2000,448(2):121-138.
2 Ma LJ, Marcantoni C, Linton MF, et al.Peroxisome proliferator-activated receptor-agonist troglitazone protects against nondiabetic glomerulosclerosis in rats[J]. Kidney International,2001,59(5):1899-1910.
3 Nicholas SB, Kawano Y, Shu Wakino, et al. Expression and function of peroxisome proliferators-activated receptor-γin mesangial cells.Hypertension,2001, 37(2 Part 2):722.
4 Bakris G, Viberti G, Weston WM,et a1 .Rosiglitazone reduces urinary albumin excretion in type 2 diabetes[J].J Hum Hypertens,2003,17(1): 7-12.
5.Guan Y,Breyer MD.Peroxisome proliferator-activated receptors (PPARs):Novel therapeutic targets in renal disease[J].Kidney Int,2001,60(1):14-30.
6贾忠辉,刘志红,郑敬民,等.大黄酸和辛伐他汀对db /db糖尿病小鼠脂代谢紊乱和肾脏保护作用的比较[J].肾脏病与透析肾移植杂志,2006,15(3):233-239.
7张学亮,郭啸华,刘志红,等.大黄酸对低剂量链脲佐菌素肥胖糖尿病大鼠糖尿病肾病的影响[J].中华内分泌代谢杂志,2005,21(6):563-565.
8 Michalik L,Wahli W.Peroxisome proliferator-activated receptors:three isotypes for a multitude of functions[J].Curr Opin Biotechnol,1999,10(6):564-570.
9 Guan Y, Breyer MD. Targeting peroxisome proliferator-activated receptors (PPARs) in kidney and urologic disease[J]. Minerva Urol Nefrol,2002,54(2):65-79.
10 Issemann I,Green S.Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators[J].Nature,1990,347(6294):645-650.
11 Desvergene B, Wahli W. Peroxisome proliferator-activated receptors: nuclear control of metabolism [J]. Endocr Rev, 1999, 20(5):649-688.
12 Ferry G,Bruneau V,Beauverger P,et a1.Binding of prostaglandins to human PPARgamma:tool assement and new natural ligands[J].Eur J Pharmaco1.2001,417(1-2):77-89.
13 Kliewer SA,Sundseth SS,Jones SA,et a1.Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptorsαandγ[J].Proc Natl Acad Sci USA,1997,94(9):4318-4323.
14 Forman BM,Chen J,Evans RM .Hypolipidemic drugs,polyunsaturated fatty acids,and eicosanoids are ligands for peroxisome proliferator-activated receptors alpha and delta[J].Proc Natl Acad Sci USA,1997,94(9):4312-4317.
15 Zhu Y,Alvares K,Huang Q,et a1.Cloning of a new member of the peroxisome proliferator-activated receptor gene family from mouse live mouse[J].J Biol Chem,1993,268(36):26817-26820.
16 Bloomgarden ZT. Diabetic nephropathy[J]. Diabetes Care, 2005, 28(3):745-751.
17 McCarthy KJ,Routh RE,Shaw W,et a1.Troglitazone halts diabetic glomerulosclerosis by blockade of mesangial expansion[J].Kidney Int,2000,58(6):2341-2350.
18 Isshiki K,Haneda M,Kova D,et a1 .Thiazolidinedione compounds ameliorate glomerular dysfunction independent of their insulin- sensitizing action in diabetic rats[J].Diabetes,2000,49(6):1022-1032.
19 Yamashita H,Nagai Y,Takamura T,et al. Thiazolidinedione derivatives ameliorate albuminuria in streptozotocin-induced diabetic spontaneous hypertensive rat[J]. Metabolism,2002,51(4):403-408.
20 Asano T.Wakisaka M,Yoshinari M ,et a1.Peroxisome proliferators-activatedreceptor gammal(PPARgamma1)expresses in rat mesangial cells and PPARgamma agonists modulate its differentiation[J].Biochim Biophy Acta,2000,1497(1):148-154.
21.Imano E,Kanda T,Nakatani Y,et al.Effeet of troglitazone on microalbuminuria in patients with incipient diabetic nephropathy[J]. Diabetes Care,1998,21(12):2135 -2139.
22 Lebovitz HE.Rosiglitazone monotherapy is effective in patients with type 2 diabetes[J].J Clin Endocrinol Metab.2001,86(1):280-288.
23 Ziyadeh FN. Mediators of diabetic renal disease: the case for TGF-βas the major mediator[J]. J Am Soc Nephrol, 2004, 15: S55-57.
24刘章锁,程根阳,宋洁,等.罗格列酮对单侧输尿管梗阻大鼠肾脏的保护作用[J].中华肾脏病杂志,2004,20(4):268-272.
25 Iwashima Y, Eto M, Horiuchi S , et al. Advanced glycation end product-induced peroxisome proliferators-activated receptor gamma gene expression in the cultured mesangial cells[J]. Biochem Biophys Res Commun,1999,264(2):441-448.
26 Sommer M, Wolf G. Rosiglitazone increases PPARγin renal tubular epithelial cells and protects against damage by hydrogen peroxide.Am J Nephrol, 2007,27(4):425-434.
27 Routh RE, Johnson JH,McCarthy KJ. Troglitazone suppresses the secretion of type I collagen by mesangial cells in vitro[J].Kidney Int,2002, 61(4):1365-1376.
28刘章锁,牛红心,程根阳,等.罗格列酮对糖尿病大鼠肾保护机制的研究[J].中华肾脏病杂志,2004,20(2):109-112.
29 Zheng F,Fornoni A,Elliot SJ,et al.Upregulation of type I collagen by TGF-βin mesangial cells is blocked by PPARγactivation[J].Am J Physiol Renal Physiol,2002,282(4):639-648.
30 Roberts AB. Molecular and cell biology of TGF-beta[J].Miner Electrolyte Metab, 1998,24(2-3):111-119.
31 Barcellos-Hoff MH. Latency and activation in the control of TGF-beta[J].J Mammary Gland Biol Neoplasia, 1996,1(4): 353-363.
32 Baricos WH ,Reed JC ,Cortez SL. Extracellular matrix degradation by cultured mesangial cells : mediators and modulators[J]. Exp Biol Med(Maywood),2003,228 (9):1018-1022.
33 Wahab NA, Schaefer L, Weston BS, et al. Glomerular expression of thrombospondin-1, transforming growth factor beta and connective tissue growth factor at different stages of diabetic nephropathy and their interdependent roles in mesangial response to diabetic stimuli[J]. Diabetologia, 2005, 48(12):2650-60.
34 Kelly DJ,Gilbert RE,Cox AJ,et al. Aminoguanidine ameliorates overexpression of prosclerotic growth factors and collagen deposition in experimental diabetic nephropathy[J].J Am Soc Nephrol 2001,12(10):2098-2107.
35 Singh LP, Green K, Alexander M,et al. Hexosamines and TGF-beta1 use similar signaling pathways to mediate matrix protein synthesis in mesangial cells[J].Am J Physiol Renal Physiol ,2004 ,286(2):F409-416.
36 Chen S, Hong SW, Iglesias-de la Cruz MC,et al. The key role of the transforming growth factor-beta system in the pathogenesis of diabetic nephropathy[J]. Ren Fail, 2001,23(3-4):471-481.
37 Yevdokimova NY, Komisarenko SV. TGFbeta1 is involved in high glucose-induced accumulation of pericellular chondroitin sulphate in human endothelial cells[J]. J Diabetes complications,2004,18 (5):300- 308.
38 Yu HT.Progression of the chronic renal failure[J].Arch Intern Med,2003,163(12):1417-1429.
39 Bottinger EP,Bitzer M.TGF-βsignaling in renal disease[J].J Am Soc Nephrol,2002,13(1O):2600-2610.
40 Douthwaite JA, Johnson TS, Haylor JL,et al. Effects of transforming growth factor-beta1 on renal extracellular matrix components and their regulating proteins[J].J Am Soc Nephrol,1999 ,10(10):2109-2119.
41 Singh R, Song RH, Alavi N, et al. High glucose decreases matrix metalloproteinase-2 activity in rat mesangial cells via transforming growth factor-beta1[J]. Exp Nephrol. 2001,9(4):249-257.
42 Gilbert RE, Cox A, Wu LL,et al. Expression of transforming growth factor-beta1 and typeⅣcollagen in the renal tubulointerstitium in experimental diabetes: effects of ACE inhibition[J]. Diabetes, 1998,47(3): 414-422.
43 Chen Y,Blom IE,Sa S,et a1. CTGF expression in mesangial cells:Involvement of SMADs,MAPK and PKC[J].Kidney Int,2002,62(4):l149-l152.
44Yokoi H ,Mukoyama H,Sugawara A,et a1. Role of connective tissure growth factor in fibronectin expression and tubulointerstial fibrosis[J].Am J Physiol,2002,282(5):F933-F942.
45 Lal MA,Brismar H,Eklof AC,et a1.Role of oxidative stress in advanced glycation end product-induced mesangial cell activation[J].Kidney Int,2002,61(6):2006-2014.
46 Daniels MC, McClain DA ,Crook ED. Transcriptional regulation of transforming growth factor betal by glucose :investigation into the role of the hexosamine biosynthesis pathway[J].Am J Med Sci,2000,319(3):138-142.
47胡志娟,李英,何伟,等.苯那普利对糖尿病大鼠肾组织中TGF-β1和Smad7表达的影响[J].中国中西医结合肾病杂志,2005,6(10):569-572.
48 Hoshi S,ShuY,Yoshida F,et al. Podocyte injury promotes progressive nephropathy in zucker diabetic fatty rats[J]. Lab Invest ,2002,82(1):25-35.
49 Erman A, Veksler S, Gafter U, et al. Renin-angiotensin system blockade prevents the increase in plasma transforming growth factor beta 1, and reduces proteinuria and kidney hypertrophy in the streptozotocin-diabetic rat[J]. J Renin Angiotensin Aldosterone Syst,2004,5(3):146-151.
50王芳,陆付耳,陈广,等.鱼腥草对链脲佐菌素诱导糖尿病大鼠肾脏TGF-β1和HGF的影响[J].中华实用中西医杂志,2006,19(14):17l3-1716.
51郭鹏,欧阳静萍,毛先晴.黄芪多糖对链唑脲霉素诱导的2型糖尿病大鼠肾脏TGF-β1表达的影响[J].微循环学杂志,2007,17(2):8-10
52贾忠辉,刘志红,郑敬民,等.大黄酸和苯那普利联合治疗db/db糖尿病小鼠的疗效观察[J].肾脏病与透析肾移植杂志,2006,15(2):112-119.
53邓悦,李才,赵贤俊,等.糖尿病大鼠肾脏PPARγmRNA表达及解毒通络保肾胶囊干预研究[J].中医药学刊,2006,24(9):1629-1631.
54龚伟,黎磊石,孙骅,等.大黄酸对糖尿病大鼠转化生长因子β及其受体表达的影响[J].肾脏病与透析肾移植杂志,2006,15(2):101-111.
55章精.刘志红亭颖健,等.大黄酸对体外培养小鼠肾小球系膜细胞葡萄转运蛋白I表达及葡萄糖摄入的影响[J].中华内分泌代谢杂志,1999,15(4):229-232.
56谭正怀,沈映君,赵军宁.大黄酸对人肾小球系膜细胞功能的影响[J].药学学报,2004,39 (11):881—886.
57张燕,薛耀明,李晨钟.罗格列酮对OLETF大鼠各组织中过氧化物酶体增殖体激活受体γ基因表达的干预作用[J].中华实验外科杂志,2005,22(6):746-749.
58 Edvardsson U, Ljungberg A, Oscarsson J. Insulin and oleic acid increase PPARgamma expression in cultured mouse hepatocytes[J]. Biochem Biophys Res Commun,2006,340 (1):111-117.
59 Lorente-Cebrián S,Pérez-Matute P, Martínez JA.Effects of eicosapentaenoic acid (EPA) on adiponectin gene expression and secretion in primary cultured rat adipocytes [J]. J Physiol Biochem, 2006,62(2):61-69.
60 Diep QN, Schiffrin EL.Increased expression of peroxisome proliferator-activated receptor-αand -γin blood vessels of spontaneously hypertensive rats[J]. Hyperten- sion, 2001,38(2):249-254.
61 de Larco JE,Todaro GJ.Growth factors from murine sarcoma virus-transformed cells[J]. Proc Natl Acad Sci U S A,1978,75(8): 4001–4005.
62 Forbes JM, Thorpe SR, Thallas-Bonke V, et al. Modulation of soluble receptor for advanced glycation end products by angiotensin-converting enzyme-1 inhibition in diabetic nephropathy[J]. J Am Soc Nephrol,2005, 16(8):2363-2372.
63 Ohga S, Shikata K, Yozai K, et al. Thiazolidinedione ameliorates renal injury in experimental diabetic rats through anti-inflammatory effects mediated by inhibition of NF-kappaB activation[J].Am J Physiol Renal Physiol, 2007,292(4):F1141-1150.
1 Michalik L,Wahli W.Peroxisome proliferator-activated receptors:three isotypes for a multitude of functions[J].Curr Opin Biotechnol,1999,10(6):564-570.
2 Guan Y, Breyer MD. Targeting peroxisome proliferator-activated receptors (PPARs) in kidney and urologic disease[J]. Minerva Urol Nefrol, 2002, 54(2):65-79.
3 Issemann I,Green S.Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators[J].Nature,1990,347(6294):645-650.
4 Desvergene B, Wahli W. Peroxisome proliferators-activated receptors: nuclear control of metabolism[J]. Endocr Rev,1999 ,20(5):649-688.
5Escher P,Wahli W .Peroxisome proliferator-activated receptors:Insight into multiple cellular functions[J].Mut Res,2000,448(2):121-138.
6Zhu Y,Alvares K,Huang Q,et a1.Cloning of a new member of the peroxisome proliferator-activated receptor gene family from mouse live mouse[J].J Biol Chem,1993,268(36):26817-26820.
7 Elbrecht A,Chen Y,Cullinan CA,et a1.Molecular cloning,expression and characterization of human peroxisome proliferator activated receptors gamma 1 and gamma 2[J].Bioehem Biophys Res Commun,1996,224(2):431-437.
8 Rocchi S,Auwerx J. Peroxisome proliferator-activated receptor-gamma: a versatile metabolic regulator[J].Ann Med, 1999, 31(5):342-351.
9 Sundvold H ,Lien S. Identification of a novel peroxisome proliferators- activated receptor (PPAR) gamma promoter in man and transactivation by the nuclear receptor ROR alpha1[J]. Biochem Biophys Res Commun, 2001, 287(2):383-390.
10 Gampe RT Jr, Montana VG, Lambert MH,et a1.Asymmetry in the PPAR- gamma/RXRalpha crystal structure reveals the molecular basis of heterodimerization among nuclear receptors[J]. Mol Cell,2000, 5(3):545-555.
11 Willson TM,Brown PJ,Sternbach DD,et a1.The PPARs:from orphan receptors to drug discovery[J].J Med Chem.2000,43(4):527-550.
12 Kliewer SA,Sundseth SS,Jones SA,et a1.Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptorsαandγ[J].Proc Natl Acad Sci U S A,1997,94(9):4318-4323.
13 Forman BM,Chen J,Evans RM .Hypolipidemic drugs,polyunsaturated fatty acids,and eicosanoids are ligands for peroxisome proliferator-activated receptors alpha and delta[J].Proc Natl Acad Sci U S A,1997,94(9):4312-4317.
14 Elbrecht A,Chen Y,Cullinan CA,et a1.Molecular cloning,expression and characterization of human pemxisome proliferator activated receptors gamma 1 and gamma 2[J].Bioehem Biophys Res Commun,1996,224(2):431-437.
15 Bocos C,Gottlicher M,Gearing K,et a1.Fatty acid activation of peroxisome proliferator-activated receptor(PPAR)[J].J Steroid Biochem Mol Biol,1995,53(1-6):467-473.
16 Nagy L,Tontonoz P,Alvarez JG,eta1.OxidizedLDL regulates macrophage gene expression through ligand activation of PPARgamma[J].cell,1998,93(2):229-240.
17 Willson TM,Brown PJ,Sternbach DD,et a1.The PPARs:from orphan receptors to drug discovery[J].J Med Chem.2000,43(4):527-550.
18 Forman BM,Tontonoz P,Chen J,et a1.15-Deoxy-delta 12,14-prostaglandin- J2 is a ligand for the adipocyte determination factor PPAR gamma[J].Ce11,1995,83(5):803-812.
19 Ferry G,Bruneau V,Beauverger P,et a1.Binding of prostaglandins to human PPARgamma:tool assement and new natural ligands[J].Eur J Pharmaco1.2001,417(1-2):77-89.
20 Berger J,BaileyP,Biswas C,et a1.Thiazolidinediones produce a conformational chang e in peroxisomal proliferator-activated receptor- gamma:binding and activation correlate with antidiabetic actions in db/db mice[J].Endocrinology,1996,137(10):4189-4195.
21 Willson TM,Cobb JE,Cowan DJ,et a1.The Structure-activity relationship between peroxisome proliferator-activated receptor gamma agonism and the antihyperglycemic activity of thiazolidinediones[J].J Med Chem,1996,39(3):665-668.
22 Harris PK,Kletzien RF.Localization of a pioglitazone response element in the adipocyte fatty acid-binding protein gene[J].Mol Pharmacol,1994,45(3):439-445.
23 Guan Y,Breyer MD.Peroxisome proliferator-activated receptors (PPARs):Novel therapeutic targets in renal disease[J].Kidney Int,2001,60(1):14-30.
24Iwashima Y, Eto M, Horiuchi S, et al. Advanced glycation end product induced peroxisome proliferators activated receptorγgene expression in the cultured mesangial cells[J]. Biochem Biophy Res Commun,1999,264(2):441.
25 Ma LJ , Marcantoni C , Linton MF, et al. Peroxisome proliferators- activated receptor-gamma agonist troglitazone protects against nondiabetic glomerulosclerosis in rats[J]. Kidney Int , 2001, 59 (5):1899-1910.
26 Nicholas SB, Kawano Y, Wakino S, et al. Expression and function of peroxisome proliferators-activated receptor-γin mesangial cells[J]. Hypertension,2001,37 (Part2) :722.
27 Bakris G,Viberti G,Weston WM,et a1 .Rosiglitazone reduces urinary albumin excretion in type 2 diabetes[J].J Hum Hypertens,2003,17(1):7-12.
28 Lebo vitz HE.Rosiglitazone monotherapy is effective in patients with type 2 diabetes[J].J Clin Endocrinol Metab.2001,86(1):280-288.
29.Imano E,Kanda T,Nakatani Y,et al.Effeet of troglitazone on microalbuminuria in patients with incipient diabetic nephropathy[J]. Diabetes Care,1998,21(12): 2135-2139
30 Bloomgarden ZT. Diabetic Nephropathy[J]. Diabetes Care, 2005, 28(3):745-751.
31McCarthy KJ,Routh RE,Shaw W,et a1.Troglitazone halts diabetic glomerulosclerosis by blockade of mesangial expansion[J].Kidney Int,2000,58(6):2341-2350.
32 Yamashita H,Nagai Y,Takamura T,et al. Thiazolidinedione derivatives ameliorate albuminuria in streptozotocin-induced diabetic spontaneous hypertensive rat [J].Metabolism,2002,51(4):403-408.
33 Asano T.Wakisaka M ,Yoshinari M ,et a1 .Peroxisome proliferator—activated receptor gammal(PPARgamma1)expresses in rat mesangial cells and PPARgamma agonists modulate its differentiation[J].Biochim Biophy Acta,2000,1497(1):148-154.
34 Isshiki K,Haneda M,Kova D,et a1 .Thiazolidinedione compounds ameliorate glomerular dysfunction independent of their insulin-sensitizing action in diabetic rats[J].Diabetes,2000,49(6):1022-1032.
35 Reilly CM,Oates JC,Cook JA,et a1.Inhibition of mesangial cell nitric oxide in MRL/Ipr mice by prostaglandin J2 and proliferator activation receptor-γagonists[J].J Immunol,2000,164(3):1498-l504.
36 Routh R E, Johnson J H, McCarhy K J.Troglitazone suppresses the secretion of type I collagen by mesangial cells in vitro [J].Kidney Int, 2002, 61(4):1365-1376.
37 Guo B, Koya D, Isono M, et al. Peroxisome proliferators activated receptor gamma ligands inhibit TGFβ1 induced fibronectin expression in glomerular mesangial cells[J].Diabetes,2004,53(1):200-208.
38Zheng F,Fornoni A,Elliot SJ,et al.Upregulation of type I collagen by TGF-βin mesangial cells is blocked by PPARγactivation[J].Am J Physiol Renal Physiol,2002,282(4):639-648.
39 Zafiriou S,Stanners SR,Saad S,et al.Pioglitazone inhibits cell growth and reduces matrix production in human kidney fibroblasts[J].J Am Soc Nephrol,2005,16(3):638- 645.
1Eto M, Saito M, Okada M, et a1.Apolipoprotein E genetic polymorphism,remnant lipoproteins,and nephropathy in type 2 diabetic patients[J].Am J Kidney Dis,2002,40:243-251.
2刘素雁,阮颖新. 2型糖尿病肾病与ApoE基因多态性的关系[J].中华肾脏病杂志,2004,2O(8): 295-296.
3 Boright AP, Paterson AD, Mirea L,et al.Genetic variation at the ACE gene is associated with persistent microalbuminuria and severe nephropathy in type 1 diabetes[J]. Diabetes , 2005, 54:1238-1244.
4刘志红,郑敬民,吴义超. db/db糖尿病肾病小鼠肾脏基因表达谱及大黄酸对其的影响[J].肾脏病与透析肾移植杂志, 2002, l1(3):201.
5贾忠辉,刘志红,郑敬民,等.大黄酸和辛伐他汀对db /db糖尿病小鼠脂代谢紊乱和肾脏保护作用的比较[J].肾脏病与透析肾移植杂志,2006,15(3):233-239.
6龚伟,黎磊石,孙骅,等.大黄酸对糖尿病大鼠转化生长因子β及其受体表达的影响[J].肾脏病与透析肾移植杂志,2006,15(2):101-111.
7刘伦志,宁建平,恩施.大黄酸对糖尿病大鼠肾小管上皮细胞表型转化的影响[J].内科急危重症杂志, 2007, 13(1):33-35.
8郭啸华,刘志红,彭艾,等.大黄酸对2型糖尿病肾病大鼠疗效观察[J].中华肾病杂志,2002,18(4):280-284.
9张学亮,郭啸华,刘志红,等.大黄酸对低剂量链脲佐菌素肥胖糖尿病大鼠糖尿病肾病的影响[J].中华内分泌代谢杂志,2005,21(6): 563-565.
10黄燕飞,刘志红,陈惠萍,等.大黄酸和罗格列酮对db/db糖尿病小鼠代谢紊乱和肾脏损伤的作用比较[J].肾脏病与透析肾移植杂志, 2004, 13(3) : 215-221.
11谭正怀,沈映君,赵军宁.大黄酸对人肾小球系膜细胞功能的影响[J].药学学报,2004,39(11):881-886.
12刘志红,朱加明,黄海东,等.大黄酸对转化生长因子诱导内皮细胞纤溶酶原激活物抑制物1表达的影响[J].中华肾脏病杂志,2002,18(5):337-341.
13 Begum N,Ragolia L.High glucose and insulin inhibit VSMC MKP-1 expression by blocking Inos via p38 MAPK activation[J]. AM J Physiol cell Physiol,2000,278:C81-C91
14郭啸华,刘志红.戴春笋,等.大黄酸抑制TGF-诱导的肾小管上皮细胞肥大及细胞外基质产生[J].肾脏病与透析肾移植杂志,2001,10(2):101-105.
15贾忠辉,刘志红,郑敬民,等.大黄酸和苯那普利联合治疗db/db糖尿病小鼠的疗效观察[J].肾脏病与透析肾移植杂志,2006,15(2):112-119.
16何东元,王笑云,王宁宁,等.大黄酸抑制肾间质成纤维细胞激活的实验研究[J].中华肾脏病杂志,2006,22(2):105.
2国家“九五”攻关计划糖尿病研究协作组.中国12个地区中老年人糖尿病患病率调查[J].中华内分泌代谢杂志,2002,18(4):280-284.
3 American Diabetes Association:Standards of medical care in diabetes-2007[J]. Diabetes Care, 2007, 30(suppl 1),S19- S21.
4Sasso FC, Nicola LD, Carbonara O, et al.Cardiovascular risk factors and disease management in type 2 diabetic patients with diabetic nephropathy[J]. Diabetes Care, 2006,29(3):498-503.
5 American Diabetes Association.Diabetic nephropathy[J].Diabetes Care, 2003,26(Suppl 1): S94-S98.
6刘志红.糖尿病肾病的治疗[J].中国实用内科杂志,2006,26(5):322-323.
7 Palmer AJ, Tucker DD, Valentine WJ, et al. Cost-effectiveness of irbesartan in diabetic nephropathy: a systematic review of published studies[J].Nephrology Dialysis Transplantation,2005,20(6):1103-1109.
8 Bloomgarden ZT. Diabetic nephropathy[J]. Diabetes Care, 2005, 28(3):745-751.
9 Beisswenger PJ, Drummond KS, Nelson RG,et al.Susceptibility to diabetic nephropathy is related to dicarbonyl and oxidative stress [J].Diabetes, 2005, 54(11):3274-3281.
10 Brownlee M. Biochemistry and molecular cell biology of diabetic complications[J]. Nature, 2001,414(6865):813-820.
11贾忠辉,刘志红,郑敬民,等.大黄酸和辛伐他汀对db/db糖尿病小鼠脂代谢紊乱和肾脏保护作用的比较[J].肾脏病与透析肾移植杂志,2006,15(3):233-239.
12张学亮,郭啸华,刘志红,等.大黄酸对低剂量链脲佐菌素肥胖糖尿病大鼠糖尿病肾病的影响[J].中华内分泌代谢杂志,2005,21(6):563-565.
13郭啸华,刘志红,李恒,等.高糖高脂饮食诱导的2型糖尿病大鼠模型及其肾病特点[J].中国糖尿病杂志, 2002,10(5):290-294.
14唐宗琼.大黄及其复方治疗糖尿病肾病的研究进展[J].四川生理科学杂志2004, 26(4): 157-158.
15游德江.生大黄粉口服加黄芪注射液静滴治疗糖尿病肾病30例临床观察[J].四川中医,2002 20(7): 38.
16李建丰.加味大黄附子汤治疗糖尿病肾病30例临床报道.中国医药导报,2006,3(18):109.
17李六生,刘建社,陈建娜.缬沙坦联合大黄治疗糖尿病肾病的临床研究[J].临床肾脏病杂志,2006,6(4):160.
18徐小鹏.大黄对糖尿病肾病伴明显蛋白尿的临床疗效[J].国外医学.中医中药分册,2003,25 (6):347.
19王雪琴,赵凤春,吴润梅.大黄制剂与苯那普利联合治疗老年2型糖尿病肾病慢性肾功能不全临床观察[J].中国药物与临床,2007,7(6):478-479.
20龚伟,黎磊石,孙骅,等.大黄酸对糖尿病大鼠转化生长因子β及其受体表达的影响[J].肾脏病与透析肾移植杂志,2006,15(2):101-111.
21刘伦志,宁建平,恩施.大黄酸对糖尿病大鼠肾小管上皮细胞表型转化的影响[J].内科急危重症杂志, 2007,13(1):33-35.
22 Mogensen CE, Christensen CK, Vittinghus E.The stages in diabetic renal disease, with emphasis on the stage of incipient diabetic nephropathy[J]. Diabetes, 1983, 32 (Suppl 2):64–78.
23 Remuzzi G, Macia M, Ruggenenti P. Prevention and treatment of diabetic renal disease in type 2 diabetes: the BENEDICT study[J]. J Am Soc Nephrol,2006,17(4 Suppl 2):S90–S97.
24 American Diabetes Association. Standards of medical care in diabetes-2008[J]. Diabetes Care, 2008,31(Suppl 1):S12-S54.
25翁建平.糖尿病肾病的诊断与治疗.临床内科杂志,2005,22(3):150-153.
26 The Diabetes Control and Complications Research Group.Effect of intensive therapy on the development and progression of diabetic nephropathy in the Diabetes Control and Complications Trial[J]. Kidney Int,1995,47(6):1703–1720.
27 UK Prospective Diabetes Study (UKPDS) Group: Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34)[J]. Lancet,1998,352(9131):854–865.
28 UK Prospective Diabetes Study Group.Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes[J]. BMJ, 1998,317(7160): 703–713.
29 Bakris GL, Williams M, Dworkin L, et al. Preserving renal function in adults with hypertension and diabetes: a consensus approach: National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group[J]. Am J Kidney Dis,2000,36(3):646–661.
30 Kasiske BL, Lakatua JD, Ma JZ,et al. A meta-analysis of the effects of dietary protein restriction on the rate of decline in renal function[J]. Am J Kidney Dis,1998,31(6):954–961.
31王保法.糖尿病肾病治疗进展.国际内分泌分册,2006,33(9):393-396.
32谷立杰.糖尿病肾病药物治疗研究进展.国际泌尿系统杂志,2006,26(5):696-701.
33 Macisaac RJ, Jerums G.Albuminuric and non-albuminuric pathways to renal impairment in diabetes[J].Minerva Endocrinol, 2005, 30(3): 161-177.
34 Dominguz LJ, Sowers JR. Metabolic syndrome therapy: prevention of vascular injury by antidiabetic agents[J]. Curr Hypertens Rep, 2005, 7(2): 110-116.
35 Dominguez JH, Tang N, Xu W,et al. Studies of renal injuryⅢ: lipid induced nephropathy in typeⅡdiabetes[J]. Kidney Int, 2000,57(1): 92-99.
36 Mazzolai L, Korber M, Bouzourene K,et al. Severe hyperlipidemia causes impaired renin-angiotensin system function in apolipoprotein E deficient mice[J]. Atherosclerosis, 2005, 186(1):86-91.
37 Blanco S,Vaquero M,Gomez-Guerrero C, et al.Potential role of angiotensin- converting enzyme inhibitors and statins on early podocyte damage in a model of type
2 diabetes mellitus, obesity, and mild hypertension[J]. Am J Hypertens, 2005, 18(4 Pt1): 557-565.
38朱加明,刘志红,黄燕飞.大黄酸对db/db小鼠糖尿病肾病疗效的观察[J].肾脏病与透析肾移植杂志, 2OO2,11(1):3-10.
39黄燕飞,刘志红,陈惠萍,等.大黄酸和罗格列酮对db/db糖尿病小鼠代谢紊乱和肾脏损伤的作用比较[J].肾脏病与透析肾移植杂志, 2004,13(3) : 215–221.
40 Kitada M,Koya D,Sugimoto T,et al.Translocation of glomerular p47phox and p67phox by protein kinase C-? activation is required for oxidative stress in diabetic nephropathy[J] .Diabetes,2003,52(10): 2603-2614.
41常洁.氧化应激及其在糖尿病肾病中的作用.国际内科学杂志,2007,34(2):105-108.
42朱斌.糖尿病氧化应激的研究进展及其与糖尿病肾病的关系[J].国外医学泌尿系统分册,2OO4,24(6):818-822.
43 Li JM, Shah AM.ROS generation by nonphagocytic NADPH oxidase: potential relevance in diabetic nephropathy[J]. J Am Soc Nephrol ,2003,14 (8 Suppl 3):S221-S226.
44 Shiose A,Kuroda J,Tsuruya K,et a1.A novel superoxide-producing NAD(P)H oxidase in kidney[J].J Biol Chem,2001,276(2):1417-1423.
45 Onozato ML,Tojo A,Goto A,et a1.Oxidative stress and nitric oxide synthase in rat diabetic nephropatby:effects of ACEI and ARB[J].Kidney Int,2OO2,61(1):186-194.
46 Wu LL, Chiou CC, Chang PY, et al. Urinary 8-OHdG: a marker of oxidative stress to DNA and a risk factor for cancer, atherosclerosis and diabetics[J]. Clin Chim Acta, 2004, 339(1-2): 1-9.
47 Chabrashvili T,TojoA,Onozato ML,et a1.Expression and cellular localization of classic NADPH oxidase subunits in the spontaneously hypertensive rat kidney[J]. Hypertension,2OO2,39(2):269-74.
48Inoguchi T, Sonta T, Tsubouchi H, et al. Protein kinase C-dependent increase in reactive oxygen species (ROS) production in vascular tissues of diabetes: role of vascular NAD(P)H oxidase[J]. J Am Soc Nephrol,2003,14(8 Suppl3):S227-S232.
49 Chung SS, Ho EC, Lam KS, et al. Contribution of polyol pathway to diabetes-induced oxidative stress [J].J Am Soc Nephrol,2003,14(8 Suppl 3):S233-S236.
50 Fukami K, Ueda S, Yamagishi S, et al. AGEs activate mesangial TGF-beta-Smad signaling via an angiotensin typeⅠreceptor interaction[J]. Kidney Int, 2004, 66(6): 2137-2147.
51 Wautier MP, Chappey O, Corda S,et al. Activation of NADPH oxidase by AGE links oxidant stress to altered gene expression via RAGE[J].Am J Physiol Endocrinol Metab, 2001,280(5):E685-E694.
52 Yim MB, Yim HS, Lee C, et al. Protein glycation: creation of catalytic sites for free radical generation[J].Ann N Y Acad Sci,2001,928(4):48-53.
53 Lal MA,Brismar H,Eklof AC,et a1.Role of oxidative stress in advanced glycation end product-induced mesangial cell activation[J].Kidney Int,2002,61(6):2006-2014.
54 Ogawa S, Mori T, NakoK, et al. AngiotensinⅡtype 1 receptor blockers reduce urinary oxidative stress markers in hypertensive diabetic nephropathy[J]. Hypert- ension, 2006, 47(4): 699-705.
55 Leehey DJ, Isreb MA, Marcic S, et al.Effect of high glucose on superoxide in human mesangial cells: role of angiotensinⅡ[J].Nephron Exp Nephrol, 2005, 100(1): e46-53.
56 NagaiY, Yao L, Kobori H, et al.Temporary angiotensin II blockade at the prediabetic stage attenuates the development of renal injury in type 2 diabetic rats.J Am Soc Nephrol, 2005, 16(3): 703-711.
57 Yavuz D,Kucukkaya B,Haklar G,et a1.Effects of captopril and losartan on lipid peroxidation, protein oxidation and nitric oxide release in diabetic rat kidney[J]. Prostaglandins Leukot Essent Fatty Acids,2OO3,69(4):223-227.
58 Tsuji T, Mizushige K, Noma T,et al. Improvement of aortic wall distensibility andreduction of oxidative stress by pioglitazone in pre-diabetic stage of Otsuka Long-Evans Tokushima fatty rats[J].Cardiovasc Drugs Ther, 2002, 16(5):429-434.
59 Tao L, Liu HR, Gao E,et al. Antioxidative, antinitrative, and vasculoprotective effects of a peroxisome proliferator-activated receptor-gamma agonist in hypercholesterolemia.[J].Circulation, 2003,108(22):2805-2811.
60 Da Ros R,Assaloni R, Ceriello A. The preventive anti - oxidant action of thiazolidinediones: a new therapeutic prospect in diabetes and insulin resistance[J]. Diabet Med, 2004, 21 (11): 1249-1252.
61 Bagi Z,Koller A,Kaley GP. PPARγactivation,by reducing oxidative stress, increases NO bioavailability in coronary arterioles of mice with Type 2 diabetes[J].Am J Physiol Heart Circ Physiol, 2004, 286(2): H742-H748.
62高苹,贾汝汉.他汀类药物非依赖降脂的肾保护作用研究新进展[J].国外医学泌尿系统分册,2004,24(1): 882-901.
63 Yang T , Chen JW , Liu CP.Combination of simvastatin and cilazapril have preventive effect on diabetic nephropathy in diabetic rat and cultured mesangial cells[J]. Diabetologia, 2001, 44( supp1):A 2651.
64蒋晓红,董吉祥.他汀类药物防治糖尿病肾病的研究现状[J].中国糖尿病杂志2007,15(5):317-318.
65 Shah S,Paparello J,Danesh FR. Effects of statin therapy on the progression of chronic kidney disease[J]. Adv Chronic Kidney Dis,2005,12(2):187-195.
66 Yu HY, Inoguchi T, Nakayama M,et al.Statin attenuates high glucose-induced and angiotensinⅡ-induced MAP kinase activity through inhibition of NAD(P)H oxidase activity in cultured mesangial cells[J]. Med Chem, 2005, 1(5): 461-466.
67 Jones SP,Teshima Y,Akao M,et a1.Simvastatin attenuated oxidant-induced mitochondrial dysfunction in cardiac myocytes[J].Circ Res,2OO3,93 (8):697-699.
68邓晓明,韩崇旭,范钰,等.糖脉宁防治糖尿病血管并发症的实验研究[J].中国中医基础医学杂志,2001,7(4): 39-41.
69廖璞,王淑琴,廖雪松,等.银杏叶提取物对糖尿病大鼠肾脏保护作用的实验研究[J].中国药房,2000,11(3): 114-116.
70何兰杰,刘萍.枸杞多糖对糖尿病大鼠肾脏氧化应激的影响[J].中国医院药学杂志,2006,26 (12): 1475-1478.
71 Craven PA, Melhem MF, Phillips SL,et al. Overexpression of Cu2+/Zn2+ superoxide dismutase protects against early diabetic glomerular injury in transgenic mice[J]. Diabetes, 2001, 50(9):2114-2125.
1Escher P,Wahli W.Peroxisome proliferator-activated receptors:Insight into multiple cellular functions[J].Mut Res,2000,448(2):121-138.
2 Ma LJ, Marcantoni C, Linton MF, et al.Peroxisome proliferator-activated receptor-agonist troglitazone protects against nondiabetic glomerulosclerosis in rats[J]. Kidney International,2001,59(5):1899-1910.
3 Nicholas SB, Kawano Y, Shu Wakino, et al. Expression and function of peroxisome proliferators-activated receptor-γin mesangial cells.Hypertension,2001, 37(2 Part 2):722.
4 Bakris G, Viberti G, Weston WM,et a1 .Rosiglitazone reduces urinary albumin excretion in type 2 diabetes[J].J Hum Hypertens,2003,17(1): 7-12.
5.Guan Y,Breyer MD.Peroxisome proliferator-activated receptors (PPARs):Novel therapeutic targets in renal disease[J].Kidney Int,2001,60(1):14-30.
6贾忠辉,刘志红,郑敬民,等.大黄酸和辛伐他汀对db /db糖尿病小鼠脂代谢紊乱和肾脏保护作用的比较[J].肾脏病与透析肾移植杂志,2006,15(3):233-239.
7张学亮,郭啸华,刘志红,等.大黄酸对低剂量链脲佐菌素肥胖糖尿病大鼠糖尿病肾病的影响[J].中华内分泌代谢杂志,2005,21(6):563-565.
8 Michalik L,Wahli W.Peroxisome proliferator-activated receptors:three isotypes for a multitude of functions[J].Curr Opin Biotechnol,1999,10(6):564-570.
9 Guan Y, Breyer MD. Targeting peroxisome proliferator-activated receptors (PPARs) in kidney and urologic disease[J]. Minerva Urol Nefrol,2002,54(2):65-79.
10 Issemann I,Green S.Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators[J].Nature,1990,347(6294):645-650.
11 Desvergene B, Wahli W. Peroxisome proliferator-activated receptors: nuclear control of metabolism [J]. Endocr Rev, 1999, 20(5):649-688.
12 Ferry G,Bruneau V,Beauverger P,et a1.Binding of prostaglandins to human PPARgamma:tool assement and new natural ligands[J].Eur J Pharmaco1.2001,417(1-2):77-89.
13 Kliewer SA,Sundseth SS,Jones SA,et a1.Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptorsαandγ[J].Proc Natl Acad Sci USA,1997,94(9):4318-4323.
14 Forman BM,Chen J,Evans RM .Hypolipidemic drugs,polyunsaturated fatty acids,and eicosanoids are ligands for peroxisome proliferator-activated receptors alpha and delta[J].Proc Natl Acad Sci USA,1997,94(9):4312-4317.
15 Zhu Y,Alvares K,Huang Q,et a1.Cloning of a new member of the peroxisome proliferator-activated receptor gene family from mouse live mouse[J].J Biol Chem,1993,268(36):26817-26820.
16 Bloomgarden ZT. Diabetic nephropathy[J]. Diabetes Care, 2005, 28(3):745-751.
17 McCarthy KJ,Routh RE,Shaw W,et a1.Troglitazone halts diabetic glomerulosclerosis by blockade of mesangial expansion[J].Kidney Int,2000,58(6):2341-2350.
18 Isshiki K,Haneda M,Kova D,et a1 .Thiazolidinedione compounds ameliorate glomerular dysfunction independent of their insulin- sensitizing action in diabetic rats[J].Diabetes,2000,49(6):1022-1032.
19 Yamashita H,Nagai Y,Takamura T,et al. Thiazolidinedione derivatives ameliorate albuminuria in streptozotocin-induced diabetic spontaneous hypertensive rat[J]. Metabolism,2002,51(4):403-408.
20 Asano T.Wakisaka M,Yoshinari M ,et a1.Peroxisome proliferators-activatedreceptor gammal(PPARgamma1)expresses in rat mesangial cells and PPARgamma agonists modulate its differentiation[J].Biochim Biophy Acta,2000,1497(1):148-154.
21.Imano E,Kanda T,Nakatani Y,et al.Effeet of troglitazone on microalbuminuria in patients with incipient diabetic nephropathy[J]. Diabetes Care,1998,21(12):2135 -2139.
22 Lebovitz HE.Rosiglitazone monotherapy is effective in patients with type 2 diabetes[J].J Clin Endocrinol Metab.2001,86(1):280-288.
23 Ziyadeh FN. Mediators of diabetic renal disease: the case for TGF-βas the major mediator[J]. J Am Soc Nephrol, 2004, 15: S55-57.
24刘章锁,程根阳,宋洁,等.罗格列酮对单侧输尿管梗阻大鼠肾脏的保护作用[J].中华肾脏病杂志,2004,20(4):268-272.
25 Iwashima Y, Eto M, Horiuchi S , et al. Advanced glycation end product-induced peroxisome proliferators-activated receptor gamma gene expression in the cultured mesangial cells[J]. Biochem Biophys Res Commun,1999,264(2):441-448.
26 Sommer M, Wolf G. Rosiglitazone increases PPARγin renal tubular epithelial cells and protects against damage by hydrogen peroxide.Am J Nephrol, 2007,27(4):425-434.
27 Routh RE, Johnson JH,McCarthy KJ. Troglitazone suppresses the secretion of type I collagen by mesangial cells in vitro[J].Kidney Int,2002, 61(4):1365-1376.
28刘章锁,牛红心,程根阳,等.罗格列酮对糖尿病大鼠肾保护机制的研究[J].中华肾脏病杂志,2004,20(2):109-112.
29 Zheng F,Fornoni A,Elliot SJ,et al.Upregulation of type I collagen by TGF-βin mesangial cells is blocked by PPARγactivation[J].Am J Physiol Renal Physiol,2002,282(4):639-648.
30 Roberts AB. Molecular and cell biology of TGF-beta[J].Miner Electrolyte Metab, 1998,24(2-3):111-119.
31 Barcellos-Hoff MH. Latency and activation in the control of TGF-beta[J].J Mammary Gland Biol Neoplasia, 1996,1(4): 353-363.
32 Baricos WH ,Reed JC ,Cortez SL. Extracellular matrix degradation by cultured mesangial cells : mediators and modulators[J]. Exp Biol Med(Maywood),2003,228 (9):1018-1022.
33 Wahab NA, Schaefer L, Weston BS, et al. Glomerular expression of thrombospondin-1, transforming growth factor beta and connective tissue growth factor at different stages of diabetic nephropathy and their interdependent roles in mesangial response to diabetic stimuli[J]. Diabetologia, 2005, 48(12):2650-60.
34 Kelly DJ,Gilbert RE,Cox AJ,et al. Aminoguanidine ameliorates overexpression of prosclerotic growth factors and collagen deposition in experimental diabetic nephropathy[J].J Am Soc Nephrol 2001,12(10):2098-2107.
35 Singh LP, Green K, Alexander M,et al. Hexosamines and TGF-beta1 use similar signaling pathways to mediate matrix protein synthesis in mesangial cells[J].Am J Physiol Renal Physiol ,2004 ,286(2):F409-416.
36 Chen S, Hong SW, Iglesias-de la Cruz MC,et al. The key role of the transforming growth factor-beta system in the pathogenesis of diabetic nephropathy[J]. Ren Fail, 2001,23(3-4):471-481.
37 Yevdokimova NY, Komisarenko SV. TGFbeta1 is involved in high glucose-induced accumulation of pericellular chondroitin sulphate in human endothelial cells[J]. J Diabetes complications,2004,18 (5):300- 308.
38 Yu HT.Progression of the chronic renal failure[J].Arch Intern Med,2003,163(12):1417-1429.
39 Bottinger EP,Bitzer M.TGF-βsignaling in renal disease[J].J Am Soc Nephrol,2002,13(1O):2600-2610.
40 Douthwaite JA, Johnson TS, Haylor JL,et al. Effects of transforming growth factor-beta1 on renal extracellular matrix components and their regulating proteins[J].J Am Soc Nephrol,1999 ,10(10):2109-2119.
41 Singh R, Song RH, Alavi N, et al. High glucose decreases matrix metalloproteinase-2 activity in rat mesangial cells via transforming growth factor-beta1[J]. Exp Nephrol. 2001,9(4):249-257.
42 Gilbert RE, Cox A, Wu LL,et al. Expression of transforming growth factor-beta1 and typeⅣcollagen in the renal tubulointerstitium in experimental diabetes: effects of ACE inhibition[J]. Diabetes, 1998,47(3): 414-422.
43 Chen Y,Blom IE,Sa S,et a1. CTGF expression in mesangial cells:Involvement of SMADs,MAPK and PKC[J].Kidney Int,2002,62(4):l149-l152.
44Yokoi H ,Mukoyama H,Sugawara A,et a1. Role of connective tissure growth factor in fibronectin expression and tubulointerstial fibrosis[J].Am J Physiol,2002,282(5):F933-F942.
45 Lal MA,Brismar H,Eklof AC,et a1.Role of oxidative stress in advanced glycation end product-induced mesangial cell activation[J].Kidney Int,2002,61(6):2006-2014.
46 Daniels MC, McClain DA ,Crook ED. Transcriptional regulation of transforming growth factor betal by glucose :investigation into the role of the hexosamine biosynthesis pathway[J].Am J Med Sci,2000,319(3):138-142.
47胡志娟,李英,何伟,等.苯那普利对糖尿病大鼠肾组织中TGF-β1和Smad7表达的影响[J].中国中西医结合肾病杂志,2005,6(10):569-572.
48 Hoshi S,ShuY,Yoshida F,et al. Podocyte injury promotes progressive nephropathy in zucker diabetic fatty rats[J]. Lab Invest ,2002,82(1):25-35.
49 Erman A, Veksler S, Gafter U, et al. Renin-angiotensin system blockade prevents the increase in plasma transforming growth factor beta 1, and reduces proteinuria and kidney hypertrophy in the streptozotocin-diabetic rat[J]. J Renin Angiotensin Aldosterone Syst,2004,5(3):146-151.
50王芳,陆付耳,陈广,等.鱼腥草对链脲佐菌素诱导糖尿病大鼠肾脏TGF-β1和HGF的影响[J].中华实用中西医杂志,2006,19(14):17l3-1716.
51郭鹏,欧阳静萍,毛先晴.黄芪多糖对链唑脲霉素诱导的2型糖尿病大鼠肾脏TGF-β1表达的影响[J].微循环学杂志,2007,17(2):8-10
52贾忠辉,刘志红,郑敬民,等.大黄酸和苯那普利联合治疗db/db糖尿病小鼠的疗效观察[J].肾脏病与透析肾移植杂志,2006,15(2):112-119.
53邓悦,李才,赵贤俊,等.糖尿病大鼠肾脏PPARγmRNA表达及解毒通络保肾胶囊干预研究[J].中医药学刊,2006,24(9):1629-1631.
54龚伟,黎磊石,孙骅,等.大黄酸对糖尿病大鼠转化生长因子β及其受体表达的影响[J].肾脏病与透析肾移植杂志,2006,15(2):101-111.
55章精.刘志红亭颖健,等.大黄酸对体外培养小鼠肾小球系膜细胞葡萄转运蛋白I表达及葡萄糖摄入的影响[J].中华内分泌代谢杂志,1999,15(4):229-232.
56谭正怀,沈映君,赵军宁.大黄酸对人肾小球系膜细胞功能的影响[J].药学学报,2004,39 (11):881—886.
57张燕,薛耀明,李晨钟.罗格列酮对OLETF大鼠各组织中过氧化物酶体增殖体激活受体γ基因表达的干预作用[J].中华实验外科杂志,2005,22(6):746-749.
58 Edvardsson U, Ljungberg A, Oscarsson J. Insulin and oleic acid increase PPARgamma expression in cultured mouse hepatocytes[J]. Biochem Biophys Res Commun,2006,340 (1):111-117.
59 Lorente-Cebrián S,Pérez-Matute P, Martínez JA.Effects of eicosapentaenoic acid (EPA) on adiponectin gene expression and secretion in primary cultured rat adipocytes [J]. J Physiol Biochem, 2006,62(2):61-69.
60 Diep QN, Schiffrin EL.Increased expression of peroxisome proliferator-activated receptor-αand -γin blood vessels of spontaneously hypertensive rats[J]. Hyperten- sion, 2001,38(2):249-254.
61 de Larco JE,Todaro GJ.Growth factors from murine sarcoma virus-transformed cells[J]. Proc Natl Acad Sci U S A,1978,75(8): 4001–4005.
62 Forbes JM, Thorpe SR, Thallas-Bonke V, et al. Modulation of soluble receptor for advanced glycation end products by angiotensin-converting enzyme-1 inhibition in diabetic nephropathy[J]. J Am Soc Nephrol,2005, 16(8):2363-2372.
63 Ohga S, Shikata K, Yozai K, et al. Thiazolidinedione ameliorates renal injury in experimental diabetic rats through anti-inflammatory effects mediated by inhibition of NF-kappaB activation[J].Am J Physiol Renal Physiol, 2007,292(4):F1141-1150.
1 Michalik L,Wahli W.Peroxisome proliferator-activated receptors:three isotypes for a multitude of functions[J].Curr Opin Biotechnol,1999,10(6):564-570.
2 Guan Y, Breyer MD. Targeting peroxisome proliferator-activated receptors (PPARs) in kidney and urologic disease[J]. Minerva Urol Nefrol, 2002, 54(2):65-79.
3 Issemann I,Green S.Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators[J].Nature,1990,347(6294):645-650.
4 Desvergene B, Wahli W. Peroxisome proliferators-activated receptors: nuclear control of metabolism[J]. Endocr Rev,1999 ,20(5):649-688.
5Escher P,Wahli W .Peroxisome proliferator-activated receptors:Insight into multiple cellular functions[J].Mut Res,2000,448(2):121-138.
6Zhu Y,Alvares K,Huang Q,et a1.Cloning of a new member of the peroxisome proliferator-activated receptor gene family from mouse live mouse[J].J Biol Chem,1993,268(36):26817-26820.
7 Elbrecht A,Chen Y,Cullinan CA,et a1.Molecular cloning,expression and characterization of human peroxisome proliferator activated receptors gamma 1 and gamma 2[J].Bioehem Biophys Res Commun,1996,224(2):431-437.
8 Rocchi S,Auwerx J. Peroxisome proliferator-activated receptor-gamma: a versatile metabolic regulator[J].Ann Med, 1999, 31(5):342-351.
9 Sundvold H ,Lien S. Identification of a novel peroxisome proliferators- activated receptor (PPAR) gamma promoter in man and transactivation by the nuclear receptor ROR alpha1[J]. Biochem Biophys Res Commun, 2001, 287(2):383-390.
10 Gampe RT Jr, Montana VG, Lambert MH,et a1.Asymmetry in the PPAR- gamma/RXRalpha crystal structure reveals the molecular basis of heterodimerization among nuclear receptors[J]. Mol Cell,2000, 5(3):545-555.
11 Willson TM,Brown PJ,Sternbach DD,et a1.The PPARs:from orphan receptors to drug discovery[J].J Med Chem.2000,43(4):527-550.
12 Kliewer SA,Sundseth SS,Jones SA,et a1.Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptorsαandγ[J].Proc Natl Acad Sci U S A,1997,94(9):4318-4323.
13 Forman BM,Chen J,Evans RM .Hypolipidemic drugs,polyunsaturated fatty acids,and eicosanoids are ligands for peroxisome proliferator-activated receptors alpha and delta[J].Proc Natl Acad Sci U S A,1997,94(9):4312-4317.
14 Elbrecht A,Chen Y,Cullinan CA,et a1.Molecular cloning,expression and characterization of human pemxisome proliferator activated receptors gamma 1 and gamma 2[J].Bioehem Biophys Res Commun,1996,224(2):431-437.
15 Bocos C,Gottlicher M,Gearing K,et a1.Fatty acid activation of peroxisome proliferator-activated receptor(PPAR)[J].J Steroid Biochem Mol Biol,1995,53(1-6):467-473.
16 Nagy L,Tontonoz P,Alvarez JG,eta1.OxidizedLDL regulates macrophage gene expression through ligand activation of PPARgamma[J].cell,1998,93(2):229-240.
17 Willson TM,Brown PJ,Sternbach DD,et a1.The PPARs:from orphan receptors to drug discovery[J].J Med Chem.2000,43(4):527-550.
18 Forman BM,Tontonoz P,Chen J,et a1.15-Deoxy-delta 12,14-prostaglandin- J2 is a ligand for the adipocyte determination factor PPAR gamma[J].Ce11,1995,83(5):803-812.
19 Ferry G,Bruneau V,Beauverger P,et a1.Binding of prostaglandins to human PPARgamma:tool assement and new natural ligands[J].Eur J Pharmaco1.2001,417(1-2):77-89.
20 Berger J,BaileyP,Biswas C,et a1.Thiazolidinediones produce a conformational chang e in peroxisomal proliferator-activated receptor- gamma:binding and activation correlate with antidiabetic actions in db/db mice[J].Endocrinology,1996,137(10):4189-4195.
21 Willson TM,Cobb JE,Cowan DJ,et a1.The Structure-activity relationship between peroxisome proliferator-activated receptor gamma agonism and the antihyperglycemic activity of thiazolidinediones[J].J Med Chem,1996,39(3):665-668.
22 Harris PK,Kletzien RF.Localization of a pioglitazone response element in the adipocyte fatty acid-binding protein gene[J].Mol Pharmacol,1994,45(3):439-445.
23 Guan Y,Breyer MD.Peroxisome proliferator-activated receptors (PPARs):Novel therapeutic targets in renal disease[J].Kidney Int,2001,60(1):14-30.
24Iwashima Y, Eto M, Horiuchi S, et al. Advanced glycation end product induced peroxisome proliferators activated receptorγgene expression in the cultured mesangial cells[J]. Biochem Biophy Res Commun,1999,264(2):441.
25 Ma LJ , Marcantoni C , Linton MF, et al. Peroxisome proliferators- activated receptor-gamma agonist troglitazone protects against nondiabetic glomerulosclerosis in rats[J]. Kidney Int , 2001, 59 (5):1899-1910.
26 Nicholas SB, Kawano Y, Wakino S, et al. Expression and function of peroxisome proliferators-activated receptor-γin mesangial cells[J]. Hypertension,2001,37 (Part2) :722.
27 Bakris G,Viberti G,Weston WM,et a1 .Rosiglitazone reduces urinary albumin excretion in type 2 diabetes[J].J Hum Hypertens,2003,17(1):7-12.
28 Lebo vitz HE.Rosiglitazone monotherapy is effective in patients with type 2 diabetes[J].J Clin Endocrinol Metab.2001,86(1):280-288.
29.Imano E,Kanda T,Nakatani Y,et al.Effeet of troglitazone on microalbuminuria in patients with incipient diabetic nephropathy[J]. Diabetes Care,1998,21(12): 2135-2139
30 Bloomgarden ZT. Diabetic Nephropathy[J]. Diabetes Care, 2005, 28(3):745-751.
31McCarthy KJ,Routh RE,Shaw W,et a1.Troglitazone halts diabetic glomerulosclerosis by blockade of mesangial expansion[J].Kidney Int,2000,58(6):2341-2350.
32 Yamashita H,Nagai Y,Takamura T,et al. Thiazolidinedione derivatives ameliorate albuminuria in streptozotocin-induced diabetic spontaneous hypertensive rat [J].Metabolism,2002,51(4):403-408.
33 Asano T.Wakisaka M ,Yoshinari M ,et a1 .Peroxisome proliferator—activated receptor gammal(PPARgamma1)expresses in rat mesangial cells and PPARgamma agonists modulate its differentiation[J].Biochim Biophy Acta,2000,1497(1):148-154.
34 Isshiki K,Haneda M,Kova D,et a1 .Thiazolidinedione compounds ameliorate glomerular dysfunction independent of their insulin-sensitizing action in diabetic rats[J].Diabetes,2000,49(6):1022-1032.
35 Reilly CM,Oates JC,Cook JA,et a1.Inhibition of mesangial cell nitric oxide in MRL/Ipr mice by prostaglandin J2 and proliferator activation receptor-γagonists[J].J Immunol,2000,164(3):1498-l504.
36 Routh R E, Johnson J H, McCarhy K J.Troglitazone suppresses the secretion of type I collagen by mesangial cells in vitro [J].Kidney Int, 2002, 61(4):1365-1376.
37 Guo B, Koya D, Isono M, et al. Peroxisome proliferators activated receptor gamma ligands inhibit TGFβ1 induced fibronectin expression in glomerular mesangial cells[J].Diabetes,2004,53(1):200-208.
38Zheng F,Fornoni A,Elliot SJ,et al.Upregulation of type I collagen by TGF-βin mesangial cells is blocked by PPARγactivation[J].Am J Physiol Renal Physiol,2002,282(4):639-648.
39 Zafiriou S,Stanners SR,Saad S,et al.Pioglitazone inhibits cell growth and reduces matrix production in human kidney fibroblasts[J].J Am Soc Nephrol,2005,16(3):638- 645.
1Eto M, Saito M, Okada M, et a1.Apolipoprotein E genetic polymorphism,remnant lipoproteins,and nephropathy in type 2 diabetic patients[J].Am J Kidney Dis,2002,40:243-251.
2刘素雁,阮颖新. 2型糖尿病肾病与ApoE基因多态性的关系[J].中华肾脏病杂志,2004,2O(8): 295-296.
3 Boright AP, Paterson AD, Mirea L,et al.Genetic variation at the ACE gene is associated with persistent microalbuminuria and severe nephropathy in type 1 diabetes[J]. Diabetes , 2005, 54:1238-1244.
4刘志红,郑敬民,吴义超. db/db糖尿病肾病小鼠肾脏基因表达谱及大黄酸对其的影响[J].肾脏病与透析肾移植杂志, 2002, l1(3):201.
5贾忠辉,刘志红,郑敬民,等.大黄酸和辛伐他汀对db /db糖尿病小鼠脂代谢紊乱和肾脏保护作用的比较[J].肾脏病与透析肾移植杂志,2006,15(3):233-239.
6龚伟,黎磊石,孙骅,等.大黄酸对糖尿病大鼠转化生长因子β及其受体表达的影响[J].肾脏病与透析肾移植杂志,2006,15(2):101-111.
7刘伦志,宁建平,恩施.大黄酸对糖尿病大鼠肾小管上皮细胞表型转化的影响[J].内科急危重症杂志, 2007, 13(1):33-35.
8郭啸华,刘志红,彭艾,等.大黄酸对2型糖尿病肾病大鼠疗效观察[J].中华肾病杂志,2002,18(4):280-284.
9张学亮,郭啸华,刘志红,等.大黄酸对低剂量链脲佐菌素肥胖糖尿病大鼠糖尿病肾病的影响[J].中华内分泌代谢杂志,2005,21(6): 563-565.
10黄燕飞,刘志红,陈惠萍,等.大黄酸和罗格列酮对db/db糖尿病小鼠代谢紊乱和肾脏损伤的作用比较[J].肾脏病与透析肾移植杂志, 2004, 13(3) : 215-221.
11谭正怀,沈映君,赵军宁.大黄酸对人肾小球系膜细胞功能的影响[J].药学学报,2004,39(11):881-886.
12刘志红,朱加明,黄海东,等.大黄酸对转化生长因子诱导内皮细胞纤溶酶原激活物抑制物1表达的影响[J].中华肾脏病杂志,2002,18(5):337-341.
13 Begum N,Ragolia L.High glucose and insulin inhibit VSMC MKP-1 expression by blocking Inos via p38 MAPK activation[J]. AM J Physiol cell Physiol,2000,278:C81-C91
14郭啸华,刘志红.戴春笋,等.大黄酸抑制TGF-诱导的肾小管上皮细胞肥大及细胞外基质产生[J].肾脏病与透析肾移植杂志,2001,10(2):101-105.
15贾忠辉,刘志红,郑敬民,等.大黄酸和苯那普利联合治疗db/db糖尿病小鼠的疗效观察[J].肾脏病与透析肾移植杂志,2006,15(2):112-119.
16何东元,王笑云,王宁宁,等.大黄酸抑制肾间质成纤维细胞激活的实验研究[J].中华肾脏病杂志,2006,22(2):105.