甘草提取液对糖尿病大鼠肾脏的保护作用
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摘要
背景及目的：糖尿病肾病(diabetic nephropathy, DN; diabetic kidney disease,DKD)是糖尿病(diabetes mellitus, DM)常见的慢性微血管并发症之一,也是导致终末期肾病(end stage renal disease, ESRD)的常见病因。因此探寻DN的发病机制和寻找早期防治药物有非常重要的临床意义和社会价值。DN的发病机制至今仍未完全阐明,近十余年随着研究的不断深入,发现DN是在遗传背景基础上糖脂代谢紊乱、血流动力学改变、氧化应激、炎症、细胞因子、生长因子等多因素综合作用的结果。既往研究证实,甘草具有抑制α-葡萄糖苷酶、降低血糖、抑制醛糖还原酶(AR)活性、抗氧化、抗炎等药理作用,对肾功能有保护作用,但有关甘草对糖尿病微血管并发症如糖尿病肾病的药理作用及其机制的研究报道较少。为此,本研究应用腹腔注射链脲佐菌素的方法复制大鼠糖尿病肾损伤模型,观察甘草提取液对糖尿病肾损伤大鼠肾功能的保护作用,并从调节肾脏AR活性、抗氧化应激、抗炎方面探讨甘草提取液抗糖尿病大鼠肾损伤、保护肾功能的作用机制。
方法：
1.制备甘草提取液。
2.分光光度法测定甘草提取液α-葡萄糖苷酶抑制活性。
3.糖尿病大鼠模型的建立及实验动物分组：雄性Wistar大鼠适应性喂养1周后,禁食12h,将链脲佐菌素(STZ)溶解于0.1mmol/L枸橼酸钠缓冲液(pH4.5),按65mg/kg腹腔内一次性注射STZ制作DM大鼠模型,共有32只大鼠成模；成模大鼠随机分为模型组和治疗组,每组16只,治疗组给予甘草提取液灌胃1次/d,每次1mL/100g体质量,连续10周；另有16只正常Wistar大鼠为对照组。
4.检测指标：于实验第2、4、6、8、10周末测定各组大鼠体重、葡萄糖氧化酶法测定空腹血糖(FBG)、考马斯亮兰法测定24h尿白蛋白量。于第10周末测定各组大鼠的肾质量指数(KI)、亲和层析法测定糖化血红蛋白(GHbAlc)、速率法测定尿、血肌酐(Scr)及血尿素氮(BUN)、高效液相色谱(HPLC)法测定血清胆固醇(TC)和甘油三酯(TG)、硫代巴比妥酸法测定血液及肾组织匀浆中丙二醛(MDA)含量、黄嘌呤氧化酶法测定血液及肾组织匀浆中超氧化物歧化酶(SOD)活性、比色法测定血液及肾组织匀浆中硒谷胱甘肽过氧化物酶(SeGSHPx)活性、DL-甘油醛-NADPH-荧光分光光度法测定红细胞及肾组织匀浆中醛糖还原酶(AR)活性、双抗体夹心ELISA法测定24h尿单核细胞趋化蛋白-1(MCP-1)含量、计算内生肌酐清除率(Ccr)。常规保存肾组织,组织切片,HE染色,光镜下观察肾组织形态学变化,免疫组织化学法观察肾脏组织MCP-1的阳性表达。
结果：
1.甘草提取液对α-葡萄糖苷酶活性抑制率为52.17%。
2.动物造模10周后,测模型组及治疗组DM大鼠KI、FBG、GHbAlC、TC、TG、Scr、BUN、Ccr、24h尿白蛋白量、24h尿MCP-1量、血液及肾组织匀浆中MDA含量、AR活性均明显高于对照组(P均<0.05),SOD、SeGSHPx活性均明显低于对照组(P均<0.05)。
3.与模型组相比,治疗组KI、FBG、GHbAlC、TC、TG、Scr、BUN、Ccr、24h尿白蛋白量、24h尿MCP-1量、血液及肾组织匀浆中MDA含量、AR活性均显著降低(P均<0.05),SOD、SeGSHPx活性均显著升高(P均<0.05)。
4.光镜下对照组肾组织未见明显改变,模型组肾小球体积和肾小球系膜面积都显著增加,肾小管肿胀,部分肾小管上皮细胞空泡变性,肾间质局灶炎性分布伴有淋巴细胞浸润,治疗组肾组织病变程度较模型组显著减轻。免疫组化显示MCP-1阳性细胞胞浆染色为棕黄色。对照组肾脏组织未见MCP-1表达或仅有微量表达,模型组肾小球毛细血管袢、系膜区及肾小管MCP-1阳性表达显著增加,治疗组肾小球毛细血管袢、系膜区及肾小管MCP-1阳性表达明显减弱(P均<0.05)。
结论：
1.甘草提取液具有α-葡萄糖苷酶抑制活性,可以降低DN大鼠血糖,调节脂代谢,减少尿蛋白。
2.甘草提取液可以抑制DN大鼠肾脏组织的氧化应激。
3.甘草提取液可以抑制DN大鼠红细胞及肾脏组织醛糖还原酶活性。
4.甘草提取液可以减少DN大鼠肾脏促炎症因子MCP-1的表达,抑制肾组织炎症反应。
Backgroud and Objective:Diabetic nephropathy is one of the common chronic microvascular complications of diabetes mellitus, and it is also a major etiology of end stage renal disease. So it is important to explore the pathogenesis of diabetic nephropathy and look for early preventing drugs. The pathogenesis of diabetic nephropathy has not yet been fully elucidated. With the deepening of the study, it is fonud that on the basis of glycolipids metabolic disorders, diabetic nephropathy is induced by hemodynamic changes, oxidative stress, inflammation, cytokines, growth factors and other factors. Previous studies have confirmed that licorice has the pharmacological effects of inhibitingα-glucosidase, decreasing fasting blood glucose(FBG), inhibiting aldose reductase(AR) activity, antioxidation and anti-inflammatory, and it has a protective effect on renal function. But we have few studys about the pharmacological effects and mechanism of licorice to microvascular complications of diabetes such as diabetic nephropathy. Therefore, in this study, we use the method of intraperitoneal injection of streptozotocin to copy the rat model of diabetic renal injury, and investigate the protective effects of licorice extracts on the kidney of diabetic rats, further discuss the mechanism from aspects of regulation of renal AR activity, antioxidation, anti-inflammatory.
Methods:
1. Licorice extracts were prepared.
2. The activity of licorice extracts to inhibitα-glucosidase was determinated by spectrophotometric method.
3. The rat model of diabetes was established and grouped:32 male wistar rats were housed in cages and fed standard pellet diet and tap water. DM was induced by a single intraperitoneal injection of streptozotocin(STZ,65mg/kg body weight) diluted in citrate buffer, pH 4.5. Rats were randomly divided into diabetic group and therapy group, each group included 16 rats. Therapy group was gavaged by licorice extracts(1mL/100g body weight) once daily for 10 weeks. Other 16 normal male wistar rats were control group.
4. Detection index:10 weeks later,24-h urine was collected for urinary creatinine, urinary albumin and urinary MCP-1. Blood was collected for FBG, GHbAlc, blood creatinine, BUN, TC, TG, MDA, SOD, SeGSHPx, AR. Ccr and KI were calculated. Kidney tissue was collected to made renal tissue homogenate to detect the content of MDA and the activity of SOD, SeGSHPx and AR. The morphological changes were observed in HE-stained sections by light microscope. The disposition of MCP-1 in kidney was detected by immunohistological staining.
Results:
1. The inhibition rate of licorice extracts toα-glucosidase was 52.17%.
2.10 weeks later, in contrast to control group, KI, Ccr, FBG, GHbAlc, Scr, BUN, TC, TG,24-h urinary albumin and 24-h urinary MCP-1 in diabetic group and therapy group were obviously increased(P<0.05).
3. In contrast to diabetic group, KI, Ccr, FBG, GHbAlc, Scr, BUN, TC, TG,24-h urinary albumin,24-h urinary MCP-1, MDA and the AR activity of blood and nephridial tissue homogenate in therapy group were obviously decreased(P<0.05). In contrast to diabetic group, the activity of SOD and SeGSHPx of blood and nephridial tissue homogenate in therapy group were obviously increased(P<0.05).
4. No significant changes in kidney tissue were observed in the control group by light microscope.In the diabetic group, we could see that glomerular volume and mesangial area were significantly increased, renal tubular swelled, vacuolar degeneration of some tubular epithelial cells, distribution of interstitial focal inflammatory. Compared with diabetic group kidney lesions in therapy group significantly reduced. We observed the strong expression of MCP-1 in renal tissue of diabetic group, while there was no or rare expression of MCP-1 in control group. By immunohistochemistry, licorice extracts suppressed the expression of MCP-1 in renal tissue(P<0.05).
Conclusion:
1. Licorice extracts could inhibite the activity of a-glucosidase, and it could also decrease the level of FBG, TC, TG and urinary albumin.
2. Licorice extracts could prevent the oxidative stress in DN.
3. Licorice extracts could inhibite the AR activity in erythrocytes and renal tissue.
4. Licorice extracts could prevent the expression of MCP-1 in the diabetic kidney and prevent the inflammatory process in DN.
方法：
1.制备甘草提取液。
2.分光光度法测定甘草提取液α-葡萄糖苷酶抑制活性。
3.糖尿病大鼠模型的建立及实验动物分组：雄性Wistar大鼠适应性喂养1周后,禁食12h,将链脲佐菌素(STZ)溶解于0.1mmol/L枸橼酸钠缓冲液(pH4.5),按65mg/kg腹腔内一次性注射STZ制作DM大鼠模型,共有32只大鼠成模；成模大鼠随机分为模型组和治疗组,每组16只,治疗组给予甘草提取液灌胃1次/d,每次1mL/100g体质量,连续10周；另有16只正常Wistar大鼠为对照组。
4.检测指标：于实验第2、4、6、8、10周末测定各组大鼠体重、葡萄糖氧化酶法测定空腹血糖(FBG)、考马斯亮兰法测定24h尿白蛋白量。于第10周末测定各组大鼠的肾质量指数(KI)、亲和层析法测定糖化血红蛋白(GHbAlc)、速率法测定尿、血肌酐(Scr)及血尿素氮(BUN)、高效液相色谱(HPLC)法测定血清胆固醇(TC)和甘油三酯(TG)、硫代巴比妥酸法测定血液及肾组织匀浆中丙二醛(MDA)含量、黄嘌呤氧化酶法测定血液及肾组织匀浆中超氧化物歧化酶(SOD)活性、比色法测定血液及肾组织匀浆中硒谷胱甘肽过氧化物酶(SeGSHPx)活性、DL-甘油醛-NADPH-荧光分光光度法测定红细胞及肾组织匀浆中醛糖还原酶(AR)活性、双抗体夹心ELISA法测定24h尿单核细胞趋化蛋白-1(MCP-1)含量、计算内生肌酐清除率(Ccr)。常规保存肾组织,组织切片,HE染色,光镜下观察肾组织形态学变化,免疫组织化学法观察肾脏组织MCP-1的阳性表达。
结果：
1.甘草提取液对α-葡萄糖苷酶活性抑制率为52.17%。
2.动物造模10周后,测模型组及治疗组DM大鼠KI、FBG、GHbAlC、TC、TG、Scr、BUN、Ccr、24h尿白蛋白量、24h尿MCP-1量、血液及肾组织匀浆中MDA含量、AR活性均明显高于对照组(P均<0.05),SOD、SeGSHPx活性均明显低于对照组(P均<0.05)。
3.与模型组相比,治疗组KI、FBG、GHbAlC、TC、TG、Scr、BUN、Ccr、24h尿白蛋白量、24h尿MCP-1量、血液及肾组织匀浆中MDA含量、AR活性均显著降低(P均<0.05),SOD、SeGSHPx活性均显著升高(P均<0.05)。
4.光镜下对照组肾组织未见明显改变,模型组肾小球体积和肾小球系膜面积都显著增加,肾小管肿胀,部分肾小管上皮细胞空泡变性,肾间质局灶炎性分布伴有淋巴细胞浸润,治疗组肾组织病变程度较模型组显著减轻。免疫组化显示MCP-1阳性细胞胞浆染色为棕黄色。对照组肾脏组织未见MCP-1表达或仅有微量表达,模型组肾小球毛细血管袢、系膜区及肾小管MCP-1阳性表达显著增加,治疗组肾小球毛细血管袢、系膜区及肾小管MCP-1阳性表达明显减弱(P均<0.05)。
结论：
1.甘草提取液具有α-葡萄糖苷酶抑制活性,可以降低DN大鼠血糖,调节脂代谢,减少尿蛋白。
2.甘草提取液可以抑制DN大鼠肾脏组织的氧化应激。
3.甘草提取液可以抑制DN大鼠红细胞及肾脏组织醛糖还原酶活性。
4.甘草提取液可以减少DN大鼠肾脏促炎症因子MCP-1的表达,抑制肾组织炎症反应。
Backgroud and Objective:Diabetic nephropathy is one of the common chronic microvascular complications of diabetes mellitus, and it is also a major etiology of end stage renal disease. So it is important to explore the pathogenesis of diabetic nephropathy and look for early preventing drugs. The pathogenesis of diabetic nephropathy has not yet been fully elucidated. With the deepening of the study, it is fonud that on the basis of glycolipids metabolic disorders, diabetic nephropathy is induced by hemodynamic changes, oxidative stress, inflammation, cytokines, growth factors and other factors. Previous studies have confirmed that licorice has the pharmacological effects of inhibitingα-glucosidase, decreasing fasting blood glucose(FBG), inhibiting aldose reductase(AR) activity, antioxidation and anti-inflammatory, and it has a protective effect on renal function. But we have few studys about the pharmacological effects and mechanism of licorice to microvascular complications of diabetes such as diabetic nephropathy. Therefore, in this study, we use the method of intraperitoneal injection of streptozotocin to copy the rat model of diabetic renal injury, and investigate the protective effects of licorice extracts on the kidney of diabetic rats, further discuss the mechanism from aspects of regulation of renal AR activity, antioxidation, anti-inflammatory.
Methods:
1. Licorice extracts were prepared.
2. The activity of licorice extracts to inhibitα-glucosidase was determinated by spectrophotometric method.
3. The rat model of diabetes was established and grouped:32 male wistar rats were housed in cages and fed standard pellet diet and tap water. DM was induced by a single intraperitoneal injection of streptozotocin(STZ,65mg/kg body weight) diluted in citrate buffer, pH 4.5. Rats were randomly divided into diabetic group and therapy group, each group included 16 rats. Therapy group was gavaged by licorice extracts(1mL/100g body weight) once daily for 10 weeks. Other 16 normal male wistar rats were control group.
4. Detection index:10 weeks later,24-h urine was collected for urinary creatinine, urinary albumin and urinary MCP-1. Blood was collected for FBG, GHbAlc, blood creatinine, BUN, TC, TG, MDA, SOD, SeGSHPx, AR. Ccr and KI were calculated. Kidney tissue was collected to made renal tissue homogenate to detect the content of MDA and the activity of SOD, SeGSHPx and AR. The morphological changes were observed in HE-stained sections by light microscope. The disposition of MCP-1 in kidney was detected by immunohistological staining.
Results:
1. The inhibition rate of licorice extracts toα-glucosidase was 52.17%.
2.10 weeks later, in contrast to control group, KI, Ccr, FBG, GHbAlc, Scr, BUN, TC, TG,24-h urinary albumin and 24-h urinary MCP-1 in diabetic group and therapy group were obviously increased(P<0.05).
3. In contrast to diabetic group, KI, Ccr, FBG, GHbAlc, Scr, BUN, TC, TG,24-h urinary albumin,24-h urinary MCP-1, MDA and the AR activity of blood and nephridial tissue homogenate in therapy group were obviously decreased(P<0.05). In contrast to diabetic group, the activity of SOD and SeGSHPx of blood and nephridial tissue homogenate in therapy group were obviously increased(P<0.05).
4. No significant changes in kidney tissue were observed in the control group by light microscope.In the diabetic group, we could see that glomerular volume and mesangial area were significantly increased, renal tubular swelled, vacuolar degeneration of some tubular epithelial cells, distribution of interstitial focal inflammatory. Compared with diabetic group kidney lesions in therapy group significantly reduced. We observed the strong expression of MCP-1 in renal tissue of diabetic group, while there was no or rare expression of MCP-1 in control group. By immunohistochemistry, licorice extracts suppressed the expression of MCP-1 in renal tissue(P<0.05).
Conclusion:
1. Licorice extracts could inhibite the activity of a-glucosidase, and it could also decrease the level of FBG, TC, TG and urinary albumin.
2. Licorice extracts could prevent the oxidative stress in DN.
3. Licorice extracts could inhibite the AR activity in erythrocytes and renal tissue.
4. Licorice extracts could prevent the expression of MCP-1 in the diabetic kidney and prevent the inflammatory process in DN.
引文
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[6]Body-White, J Williams JC. Effect of cross-linking on matrix permeability:a model for AGE-modified bosement membranes. Kidney Int, 1996,46(3):348-353.
[7]Beisswenger PJ, Maklta Z, Curphey TJ, et al. Formaiton for immunochemical advanced glycosylation end products precedes and correlates with early manifestations of renal and retinal disease in diabetes[J]. Diabetes,1995,44(7):824-829.
[8]李才,侯芳玉,刘忠英.糖基化终产物形成抑抑制剂研究的进展[J].中国新药杂志,2001,10：85-88.
[9]Oldfield MD, Bach LA, Forbes JM, et al. Advanced glycation end products cause epithelial myofibroblast transdiferentiation via the receptorfor advanced glycation end products (RAGE) [J]. Clin Invest,2001,108(12): 1853—1863.
[10]Heidland A, Sdbekova K, Schinxel R. Advance glycation end products and the progressive coulse of renal disease[J]. AmJ Kidney Dis,2001, 38(4):100-104.
[11]Krolewski M, Eggers P, Warram J H, et al. Magnitude of End-stage Renal Disease in IDDM:a 35 Year Follow-up Study [J]. Kidney Int,1996,50: 2041—2046.
[12]邵咏红,黄英伟,陈劲松,等.血管紧张素转化酶基因多态性与糖尿病及其肾脏合并症发病的关系.中华肾脏病杂志,1999,15(1)：369-371.
[13]Wladyslaw G, Dariusz K, Moczulski, Met al. Role of GLUT1 gene in susceptibility to diabetic nephropathy in type 2 diabetes. Kidney Int, 2001,59:631-636.
[14]余敏,周宏灏,刘昭前.糖尿病肾病相关基因研究进展[J].中国药理学通报,2008,24(11)：1419-1422.
[15]Green K, Brand MD, Murphy MP. Prevention of mitochondrial oxidative damage as a therapeutic sfrategy in diabetes [J]. Diabetes,2004,53(1): 110-118.
[16]Gorin Y, Block K, Hernandez J, et al. Nutrophils NADPH oxidase mediates hypertrophy and fibronectin expression in the diabetic kidney. Biol chem, 2005,280(47):39616-39626.
[17]Sonta T, Inoguchi T, Tsubouchi H, et al. Evidence for contribution of vascular NADPH oxidase to increased oxidative stress in animal models of diabetes and obesity. Free Radic Biol Med,2004,37(1):115-123.
[18]Fukami K, Ueda S, Yamagishi S, et al. AGEs activate mesangial TGF-β/Smad signaling via an angiotension type I receptor interaction. Kidney Int.2004,66(6):2137-2147.
[19]Yoo CW, Song CY, Kim BC, et al. Glycated albumin induces superoxide generation in mesangial cells. Cell Physiol Biochem,2004,14(4):361-368.
[20]Price S A, Agthong S, MiddlemasA B, et al. Mitogen-activated protein kinase p38 mediates reduced nerve conduction velocity in experimental diabetic neuropathy interactions with aldose reductase[J]. Diabetes, 2004,53 (7):1851-1856.
[21]Kitada M, Koya D, Sugimoto T, et al. Translocation of glomerular p47phox and p67phox by PKC-β activation is required for oxidative stress in diabetic nephropathy. Diabetes,2003,52(10):2603-2614.
[22]Aksun AS, Ozmen B, Ozmen D, et al. Serum and Hnary nitric oxide in Type 2 diabetes with or without microalbuminuria:relation to glomerular hyperfiltration. Diabetes Complications,2003,17(6):343-348.
[23]Susztak K, Raft AC, Schiffer M, et al. Glucose-induced reactive oxygen species cause apoptosis of podocytes and podocyte depletion at the onset of diabetic nephropathy. Diabetes,2006,55(1):225-233.
[24]Lee EA, Se JY, Jiang Z, et al. Reaction oxyen species mediate high glucose induced plasminogen activator inhibitor-1 regulation in mesangial cells and in diabetic kidney. Kidney International 2005,67 (5): 1762-1771.
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[40]刘淑贤.糖尿病患者血浆内皮素水平及其与微血管病变的关系[J].临床内科杂志,2005,22(4)：268—269.
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[1]Price S A, Agthong S, MiddlemasA B, et al. Mitogen-activated protein kinase p38 mediates reduced nerve conduction velocity in experimental diabetic neuropathy interactions with aldose reductase[J]. Diabetes, 2004,53 (7):1851-1856.
[2]涂晓文,关广聚,邹海蓉,等.蛋白激酶C在实验性糖尿病肾病早期的作用[J].中国糖尿病杂志,2003,11(4)：295-296.
[3]Inoguchi T, Yu HY, Menne J, et al. Ahered gap junction activity in cardiovascular tissues of diabetes. Med Electron Microse,2001,34(2): 86-91.
[4]Dunlop M. Aldose reductase and the role of the polyol pathway indiabetic nephropathy. Kidney Int,2000,77:3-12.
[5]Okada s, Shikata K. Intercellular adhesion molecule-1 deficient miceare resistant against renal injury after induction of diabetes[J]. Diabetes,2003,52(10):2586-2588.
[6]Body-White, J Williams JC. Effect of cross-linking on matrix permeability:a model for AGE-modified bosement membranes. Kidney Int, 1996,46(3):348-353.
[7]Beisswenger PJ, Maklta Z, Curphey TJ, et al. Formaiton for immunochemical advanced glycosylation end products precedes and correlates with early manifestations of renal and retinal disease in diabetes[J]. Diabetes,1995,44(7):824-829.
[8]李才,侯芳玉,刘忠英.糖基化终产物形成抑抑制剂研究的进展[J].中国新药杂志,2001,10：85-88.
[9]Oldfield MD, Bach LA, Forbes JM, et al. Advanced glycation end products cause epithelial myofibroblast transdiferentiation via the receptorfor advanced glycation end products (RAGE) [J]. Clin Invest,2001,108(12): 1853—1863.
[10]Heidland A, Sdbekova K, Schinxel R. Advance glycation end products and the progressive coulse of renal disease[J]. AmJ Kidney Dis,2001, 38(4):100-104.
[11]Krolewski M, Eggers P, Warram J H, et al. Magnitude of End-stage Renal Disease in IDDM:a 35 Year Follow-up Study [J]. Kidney Int,1996,50: 2041—2046.
[12]邵咏红,黄英伟,陈劲松,等.血管紧张素转化酶基因多态性与糖尿病及其肾脏合并症发病的关系.中华肾脏病杂志,1999,15(1)：369-371.
[13]Wladyslaw G, Dariusz K, Moczulski, Met al. Role of GLUT1 gene in susceptibility to diabetic nephropathy in type 2 diabetes. Kidney Int, 2001,59:631-636.
[14]余敏,周宏灏,刘昭前.糖尿病肾病相关基因研究进展[J].中国药理学通报,2008,24(11)：1419-1422.
[15]Green K, Brand MD, Murphy MP. Prevention of mitochondrial oxidative damage as a therapeutic sfrategy in diabetes [J]. Diabetes,2004,53(1): 110-118.
[16]Gorin Y, Block K, Hernandez J, et al. Nutrophils NADPH oxidase mediates hypertrophy and fibronectin expression in the diabetic kidney. Biol chem, 2005,280(47):39616-39626.
[17]Sonta T, Inoguchi T, Tsubouchi H, et al. Evidence for contribution of vascular NADPH oxidase to increased oxidative stress in animal models of diabetes and obesity. Free Radic Biol Med,2004,37(1):115-123.
[18]Fukami K, Ueda S, Yamagishi S, et al. AGEs activate mesangial TGF-β/Smad signaling via an angiotension type I receptor interaction. Kidney Int.2004,66(6):2137-2147.
[19]Yoo CW, Song CY, Kim BC, et al. Glycated albumin induces superoxide generation in mesangial cells. Cell Physiol Biochem,2004,14(4):361-368.
[20]Price S A, Agthong S, MiddlemasA B, et al. Mitogen-activated protein kinase p38 mediates reduced nerve conduction velocity in experimental diabetic neuropathy interactions with aldose reductase[J]. Diabetes, 2004,53 (7):1851-1856.
[21]Kitada M, Koya D, Sugimoto T, et al. Translocation of glomerular p47phox and p67phox by PKC-β activation is required for oxidative stress in diabetic nephropathy. Diabetes,2003,52(10):2603-2614.
[22]Aksun AS, Ozmen B, Ozmen D, et al. Serum and Hnary nitric oxide in Type 2 diabetes with or without microalbuminuria:relation to glomerular hyperfiltration. Diabetes Complications,2003,17(6):343-348.
[23]Susztak K, Raft AC, Schiffer M, et al. Glucose-induced reactive oxygen species cause apoptosis of podocytes and podocyte depletion at the onset of diabetic nephropathy. Diabetes,2006,55(1):225-233.
[24]Lee EA, Se JY, Jiang Z, et al. Reaction oxyen species mediate high glucose induced plasminogen activator inhibitor-1 regulation in mesangial cells and in diabetic kidney. Kidney International 2005,67 (5): 1762-1771.
[25]Wang X, Shaw S, Amiri F, el al. Inhibition of the JAK/STAT signaling pathway prevents the high glucose-induced increase in TGF-β and fibronectin syrahesis in mesangial cells. Diabetes,2002,51(12): 3505-3509.
[26]Ha H, Yu MR, Choi YJ, et al. Role of high glucose-induced nuclear factor-kappaB activation in monocyte chemoattractant protein-1 expression by mesangial cells. Am Soc Nephrol,2002,13(4):894—902.
[27]邹丽霞,谷卫.环氧化酶-2与糖尿病[J]国际内分泌代谢杂志,2006,26(1)：45-47.
[28]Jin Y, Moriya T, Tanaka K, et al. Glumcmlar hyperfiltration in non-proteinuric and non-hypertensive Japanese type 2 diabetic patients. Diabetes Rrs Clin Pract,2005:23(2):17-20.
[29]Isono M, Mogyorosi A, Han DC, et al. Stimulation of TGF-β Ⅱ receptor by high glucose in mouse mesangial cells and in diabetic kidney. Renal Physiol,2000,278(5):830-838.
[30]Singh R, Song RH, Alavi N, et al. High glucose decreases matrix metalloproteinase-2 activity in rat mesanginal cells via transforming growth factor-β. Exp Nephrol,2001,9(4):249—257.
[31]Mclennan SV, Fisher E, MarteLl SY, et al. Efects of glucose on matrix metalloproteinase a plasmin activities in mesangial ceLls:possible in diabetic nephropathy. Kidney Int,2000,77(1):81-87.
[32]刘颖慧.TNF-α与糖尿病肾病[J].国外医学·内分泌学分册。2002,22(4)：253-255.
[33]Kanesaki Y, Suzuki D, Uehara G, et al. Vascular endothelial growth factor gene expression is correlated with glomerular neovascularization in human diabetic nephropathy [J]. Am J Kidney Dis,2005,45(2):288-294.
[34]Wolf G, Chen S, Ziyadeh FN. From the periphery of glumeruLar capillary wall toward the center of disease:podocyte injury comes of age in diabetic nephropathy. Diabetes,2005,54(6):1626-1634.
[35]Yokoi H, Mukoyama M, Mori K. Overexpression of connective tissue growth factor in podocytes worsens diabetic nephropathy in mice[J]. Kidney Int, 2008,73(4):446-455.
[36]Chen Y, Abraham DJ, Xu Shi-wen, et al. CCN2 (Connective Tissue Growth Factor) promotes fibroblast adllesion to fibronectin. Mol Biol Cell, 2004,15(12):5635-5646.
[37]Liu XC, Liu BC, Zhang XL, et al. Role of ERK1/2 and PI3-K in the regulation of CTGF-induced ILK expression in HK-2 cells. Clin Chim Acta, 2007,382:89-94.
[38]Burns WC, Twigg, SM, Forbes JM, et al. Connective tissue growth factor plays important role in advanced glycation end product-induced tubular epithelial to mesenchy transition:implication for diabetic renal disese[J]. JAm Soc Nephrol,2006,17(9):2484—2494.
[39]张延峰,王桂英.内皮素与糖尿病的关系及临床意义[J].现代预防医学,2005,32(6)：696.
[40]刘淑贤.糖尿病患者血浆内皮素水平及其与微血管病变的关系[J].临床内科杂志,2005,22(4)：268—269.
[41]Miller-Kaspllak E, Niemir ZI, Czekalski S. The role of platelet-derived growth factor-A(PDGF-A)in hypertension and renal disease. Pol Merkuriusz Lek,2004.16(94):403-405.
[42]Kelly DJ, Gilbert RE. Aminoguanidine ameliorates overexpression of prosclerotic growth factors and collagen deposition in experimental diabetic nephropathy. J Am Soe Nephrol,2001,12(10):2098-2107.
[43]Deuther-Conrad W, Franke S, et al. In vitro-prepared advanced glycation end-products and the modulating potential of their low-molecular weight degradation products in IRPTCA rat proximal-tubular derived kidney epithelial cell line. Cell Mol Bid,2001,47:187-196.
[44]Taneda S, Hudldns KI, et al. Growth factor expression in a murine model of cryoglobulinemia. Kidney Int,2003,63(2):576-590.
[45]Makillo H, Sugiyama H, Kashihara N. Apoptosis and extracellular matrix-cell interactions in kidney disease, kidney Int Suppl,2000,77: 67-75.
[46]Fraser D, Wakefield L, Phillips A. Independent regulation of transforming growth factor-β transcription and translation by glucose and platelet-derived growth factor. Am J Pathol,2002,161(3):1039-1049.
[47]Schreiber BD, Huglles ML, Groggel GC. Insulin-like growth factor-1 stimulates production of mesangial cell matrix components. Clin Nephrol, 1995,43:368-374.
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