梓醇对糖尿病大鼠肾脏IGF-1和Akt表达的影响
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摘要
目的:糖尿病肾病(diabetic nephropathy, DN)是糖尿病微血管并发症之一。其发病的分子机制尚未十分明确,胰岛素样生长因子(insulin-like growth factor-1, IGF-1)在糖尿病肾组织的高表达导致肾小球基底膜增厚、细胞外基质增生和肾小球硬化是DN的可能机制之一。本研究小组前期研究发现中药活性单体梓醇(Catalpol)对糖尿病大鼠周围神经(糖尿病微血管病变)具有保护作用,但梓醇在DN防治中的作用尚未见报道。本研究旨在观察IGF-1及其下游信号传导通路磷脂酰肌醇3激酶(phosphatidylinositol 3 kinase, PI3K)/蛋白激酶B或Akt(protein kinase B,PKB/Akt)在DN的发生、发展中的变化,探讨梓醇能否通过调控糖尿病大鼠肾脏IGF-1和Akt的表达发挥对DN的防治作用,为研发临床治疗DN的新药提供理论依据。
方法:健康雄性Sprague-Dawley(SD)大鼠36只随机分为正常对照组(NC组)、糖尿病对照组(DM组)、糖尿病梓醇干预组(DT组)各12只。通过链脲佐菌素(streptozotocin,STZ)一次性腹腔注射的方式(50mg/kg体重)建立糖尿病大鼠模型。动物成模后随机分为DM组和DT组。第8～10周,DT组腹腔注射梓醇(5mg/kg体重),每日1次,共计2周;NC组和DM组注射等体积生理盐水。8周、10周点各组大鼠入代谢笼收集24h尿,测24h尿白蛋白排泄量(UAE)、尿微量白蛋白(MA)、尿肌酐(Cre)值,计算尿MA/Cre值。11周点处死大鼠,心脏取血用于糖化血红蛋白(HbA1c)、血肌酐(Scr)、尿素氮(BUN)测定、计算肌酐清除率(Ccr),取双肾计算肾重/体重比值(KW/BW),左肾用于HE、PAS、PASM染色观察大鼠肾脏病理改变以及免疫组化(immunohistochemstry, IHC)检测大鼠IGF-1和Akt1的表达;右肾用于分子生物学检测,以反转录-聚合酶链式反应(reverse transcription- polymerase chain reaction,RT-PCR)方法检测IGF-1、Akt1 mRNA表达,用蛋白质免疫印迹法(Western blot)检测p-Akt蛋白水平的表达。
结果:
1.体重(g)、血糖(mmol/L)和HbA1c(%):成模10周时,DM组和DT组大鼠体重分别为266.77±55.47和279.50±43.56,增长幅度小于NC组的356.22±50.73(P<0.001);NC组大鼠血糖(5.72±1.22)、HbA1c(3.30±0.10)保持在正常范围内,DM组和DT组血糖分别为25.37±3.56和23.54±8.70,HbA1c分别为5.92±0.72和6.12±0.07,均显著高于NC组(P<0.001);而DM组和DT组的体重、血糖和HbA1c无统计学意义(P>0.05)。
2.肾功能及肾重/体重比:糖尿病大鼠的肾功能受累,成模10周时,DM组与DT组大鼠尿MA/Cre(mg/mmol)分别为17.35±3.51和15.54±3.57,较NC组(3.79±1.02)明显升高(P<0.001);DM组与DT组UAE(mg/24h)分别为1.00±0.21和0.81±0.34,较NC组(0.21±0.06)升高(P<0.05);DM组与DT组相对肾重(%)分别为6.09±0.91和5.93±0.69,较NC组(4.03±0.50)明显升高(P<0.001);DT组较DM组有所降低,但没有统计学差异(P>0.05)。各组血肌酐、肌酐清除率值无明显的统计学意义(P>0.05)。
3.肾组织病理变化:PAS及PASM染色显示,DM组大鼠肾小球系膜基质明显增多,系膜细胞增生,基底膜增厚,少数表现为结节性肾小球硬化改变,符合糖尿病肾病病变特征。而治疗组上述病理改变均有不同程度减轻。
4. RT-PCR:DM组IGF-1 mRNA表达量(0.52±0.17)较NC组(0.38±0.11)明显上调(P<0.05),DT组表达量(0.42±0.21)较NC组差异无显著性(P>0.05)。DM和DT组的Akt1 mRNA表达量分别为1.02±0.58和0.89±0.34,较NC组(0.56±0.19)明显增多(P<0.05),DT组的表达量低于DM组(P<0.05)。
5. Western blot:各组大鼠肾组织Akt总蛋白表达丰富,DM组大鼠肾组织Akt磷酸化水平(0.86±0.08)明显升高,与NC组(0.42±0.11)比较差异显著(P<0.001),DT组大鼠p-Akt水平(0.65±0.06)较DM组降低(P<0.05)。
6.免疫组化:IGF-1和Akt1在各组肾小球、近曲小管、集合管中均有阳性表达,DM组IGF-1表达水平(10.35±0.73)与NC组(4.81±0.62)比较显著增加( P<0.001), DT组( 5.63±1.77)较DM组显著减少(P<0.001);DM组及DT组Akt1的表达量分别为15.49±2.33和9.20±1.27,与NC组(3.01±1.13)比较显著增加(P<0.001),DT组较DM组显著减少(P<0.001)。
结论:
1. STZ诱导糖尿病大鼠成模8周时,其肾功能即出现异常并逐渐出现肾小球基底膜增厚,系膜基质增生等病理改变。
2. IGF-1在糖尿病大鼠肾组织的高表达对糖尿病肾病的发生发展起到重要作用,这种作用部分是通过PI3K/Akt信号通路实现的。
3.梓醇可部分下调糖尿病大鼠肾脏IGF-1和Akt的表达,一定程度减轻糖尿病肾病病理改变,但对糖尿病大鼠24h尿白蛋白、尿MA/Cre及肾功能指标影响不明显。
Objective Diabetic nephropathy is one of the important chronic microvascular complications of diabetes. However, the molecular details of diabetic nephropathy are still poorly understood. Glomerular basement membrane thickening, extracellular matrix proliferation and glomerulo- sclerosis caused by insulin-like growth factor-1 accumulation in kidney may play major roles in diabetic nephropathy. Catapol, one of the main active ingredient in rehmannia, exerted neuroprotective effects in diabetic peripheral neuropathy (a diabetic microangiopathy) in diabetic rats in our previous study, while it hasn’t been reported on the research about diabetic nephropathy. The present study was performed to investigate the pathogenesis of IGF-1 and PI3K/Akt signal pathway in diabetic nephro- pathy and observe whether catapol could protect renal function through regulating the expression of IGF-1. Moreover, it could provide a clue of traditional Chinese medicine in clinical application.
Methods Male Sprague-Dawley (SD) rats were randomly divided into three groups: normal control group (NC), diabetic control group (DM) and diabetic group treated with catapol (DT) including 12 rats for each group. The diabetic rat models were induced by intraperitoneal injection of streptozotocin (STZ) (50mg/kg). Since 8th week point, the rats of DT group were administered with catapol (5mg/kg) by intraperitoneal injection once daily for 2 weeks, while the other two groups were injected with equal volume of normal saline. All rats were in metablic cage to collect 24h urine samples for urinary albumin excretion (UAE), urine microalbumin (MA), urine creatinine (Cre) testing and MA/Cre calculating at the 8th and 10th week. The next day after ten-week, before sacrificed, rats’blood was sampling from heart for measuring HbA1c, BUN, Scr levels and Ccr calculating. Then the kidneys were removed quickly for measuring relative kidney weight (KW/BW). The left kidney was dyed by HE, PAS and PASM to observe pathologic morphology and detected the expression of IGF-1 and Akt1 by immunohistochemistry. While the right kidney was used to detect the change of IGF-1 and Akt at both the levels of mRNA and protein.
Results
1. Body weight (g), Blood glucose (mmol/L) and HbA1C (%): At the 10th week, mean weights of DM group (266.77±55.47) and DT group (279.50±43.56) were significantly lower (P <0.001) than the NC group (356.22±50.73); Blood glucose and HbA1C of DM (25.37±3.56&5.92±0.72) and DT group (23.54±8.70&6.12±0.07) were significantly higher (P<0.001) than that of NC group, while the blood glucose and HbA1C were normal in the NC group (5.72±1.22&3.30±0.10), but there was no significant difference (P >0.05) between DM and DT group on body weight, blood glucose and HbA1C.
2. Renal function and relative kidney weight: At the 10th week, the values of MA/Cre (mg/mmol) for DM group (17.35±3.51) and DT group (15.54±3.57) were markedly higher (P<0.001) than that of NC group (3.79±1.02); The levels of 24h urinary albumin excretion (mg/24h) for DM group (1.00±0.21) and DT group (0.81±0.34) were significant higher (P<0.05) than that of NC group (0.21±0.06); The relative kidney weight (%) in DM (6.09±0.91) and DT group (5.93±0.69) were significantly higher (P<0.001) than that in NC group (4.03±0.50). The data of DT group was lower than that of DM group, but there was no significant difference (P>0.05). Scr and Ccr levels were normal in each group (P >0.05).
3. Histopathological assessment: In PAS and PASM dyed slides, diabetic non-treated rats showed proliferation of mesangial cells, with expansion of mesangial matrix, as well as thickening of ECM. Classic change in DN such as sclerotic nodule formation in glomeruli was observed. But the above pathology change obviously reduced in DT group.
4. RT-PCR: In renal tissue, the expression of IGF-1 mRNA in DM group (0.57±0.17) increased significantly (P <0.05) than NC group (0.38±0.11) while there was no significant difference (P >0.05) between the DT (0.42±0.21) and NC group. The expression of Akt1 mRNA of DM (1.02±0.58) and DT group (0.89±0.34) increased significantly (P <0.05) than NC group (0.56±0.19), while the level of DT group was significantly lower (P<0.05) than DM group.
5. Western blotting: Western blotting showed the activity of p-Akt was increased (P <0.001) in DM group (0.86±0.08) and DT group (0.65±0.06) compared with that of NC group (0.42±0.11), and it was markedly down-regulated (P <0.05) in DT group than DM group.
6. Immunohistochemistry: In all three groups, renal glomerulus, proximal convoluted tubule and collecting tube were showing positive localization. The average optical density (AOD) of IGF-1 in DM group (10.35±0.73) was significantly increased (P <0.001) than NC group(4.81±0.62), but the AOD of DT group (5.63±1.77) was markedly lower (P<0.001) than DM group. The AOD of Akt1 in DM (15.49±2.33) and DT group (9.20±1.27) were both higher (P <0.001) than NC group (3.01±1.13), while the AOD of DT was lower (P <0.001) than DM group.
Conclution
1. The renal function was gradually impaired and the pathology of glomerular basement membrane thickening and extracellular matrix proliferation were observed at the 8th week after the onset of diabetes.
2. The over-expression of IGF-1 in diabtic rats played a major role in DN, at least in part, by activation of PI3K/Akt signal pathway.
3. Catapal could down-regulate IGF-1 and Akt activities and reduce the pathology changes in diabetic kidney to a certain extent, however there was no exact improvement in 24h urinary albumin excretion, MA/Cre and renal fuction values.
方法:健康雄性Sprague-Dawley(SD)大鼠36只随机分为正常对照组(NC组)、糖尿病对照组(DM组)、糖尿病梓醇干预组(DT组)各12只。通过链脲佐菌素(streptozotocin,STZ)一次性腹腔注射的方式(50mg/kg体重)建立糖尿病大鼠模型。动物成模后随机分为DM组和DT组。第8～10周,DT组腹腔注射梓醇(5mg/kg体重),每日1次,共计2周;NC组和DM组注射等体积生理盐水。8周、10周点各组大鼠入代谢笼收集24h尿,测24h尿白蛋白排泄量(UAE)、尿微量白蛋白(MA)、尿肌酐(Cre)值,计算尿MA/Cre值。11周点处死大鼠,心脏取血用于糖化血红蛋白(HbA1c)、血肌酐(Scr)、尿素氮(BUN)测定、计算肌酐清除率(Ccr),取双肾计算肾重/体重比值(KW/BW),左肾用于HE、PAS、PASM染色观察大鼠肾脏病理改变以及免疫组化(immunohistochemstry, IHC)检测大鼠IGF-1和Akt1的表达;右肾用于分子生物学检测,以反转录-聚合酶链式反应(reverse transcription- polymerase chain reaction,RT-PCR)方法检测IGF-1、Akt1 mRNA表达,用蛋白质免疫印迹法(Western blot)检测p-Akt蛋白水平的表达。
结果:
1.体重(g)、血糖(mmol/L)和HbA1c(%):成模10周时,DM组和DT组大鼠体重分别为266.77±55.47和279.50±43.56,增长幅度小于NC组的356.22±50.73(P<0.001);NC组大鼠血糖(5.72±1.22)、HbA1c(3.30±0.10)保持在正常范围内,DM组和DT组血糖分别为25.37±3.56和23.54±8.70,HbA1c分别为5.92±0.72和6.12±0.07,均显著高于NC组(P<0.001);而DM组和DT组的体重、血糖和HbA1c无统计学意义(P>0.05)。
2.肾功能及肾重/体重比:糖尿病大鼠的肾功能受累,成模10周时,DM组与DT组大鼠尿MA/Cre(mg/mmol)分别为17.35±3.51和15.54±3.57,较NC组(3.79±1.02)明显升高(P<0.001);DM组与DT组UAE(mg/24h)分别为1.00±0.21和0.81±0.34,较NC组(0.21±0.06)升高(P<0.05);DM组与DT组相对肾重(%)分别为6.09±0.91和5.93±0.69,较NC组(4.03±0.50)明显升高(P<0.001);DT组较DM组有所降低,但没有统计学差异(P>0.05)。各组血肌酐、肌酐清除率值无明显的统计学意义(P>0.05)。
3.肾组织病理变化:PAS及PASM染色显示,DM组大鼠肾小球系膜基质明显增多,系膜细胞增生,基底膜增厚,少数表现为结节性肾小球硬化改变,符合糖尿病肾病病变特征。而治疗组上述病理改变均有不同程度减轻。
4. RT-PCR:DM组IGF-1 mRNA表达量(0.52±0.17)较NC组(0.38±0.11)明显上调(P<0.05),DT组表达量(0.42±0.21)较NC组差异无显著性(P>0.05)。DM和DT组的Akt1 mRNA表达量分别为1.02±0.58和0.89±0.34,较NC组(0.56±0.19)明显增多(P<0.05),DT组的表达量低于DM组(P<0.05)。
5. Western blot:各组大鼠肾组织Akt总蛋白表达丰富,DM组大鼠肾组织Akt磷酸化水平(0.86±0.08)明显升高,与NC组(0.42±0.11)比较差异显著(P<0.001),DT组大鼠p-Akt水平(0.65±0.06)较DM组降低(P<0.05)。
6.免疫组化:IGF-1和Akt1在各组肾小球、近曲小管、集合管中均有阳性表达,DM组IGF-1表达水平(10.35±0.73)与NC组(4.81±0.62)比较显著增加( P<0.001), DT组( 5.63±1.77)较DM组显著减少(P<0.001);DM组及DT组Akt1的表达量分别为15.49±2.33和9.20±1.27,与NC组(3.01±1.13)比较显著增加(P<0.001),DT组较DM组显著减少(P<0.001)。
结论:
1. STZ诱导糖尿病大鼠成模8周时,其肾功能即出现异常并逐渐出现肾小球基底膜增厚,系膜基质增生等病理改变。
2. IGF-1在糖尿病大鼠肾组织的高表达对糖尿病肾病的发生发展起到重要作用,这种作用部分是通过PI3K/Akt信号通路实现的。
3.梓醇可部分下调糖尿病大鼠肾脏IGF-1和Akt的表达,一定程度减轻糖尿病肾病病理改变,但对糖尿病大鼠24h尿白蛋白、尿MA/Cre及肾功能指标影响不明显。
Objective Diabetic nephropathy is one of the important chronic microvascular complications of diabetes. However, the molecular details of diabetic nephropathy are still poorly understood. Glomerular basement membrane thickening, extracellular matrix proliferation and glomerulo- sclerosis caused by insulin-like growth factor-1 accumulation in kidney may play major roles in diabetic nephropathy. Catapol, one of the main active ingredient in rehmannia, exerted neuroprotective effects in diabetic peripheral neuropathy (a diabetic microangiopathy) in diabetic rats in our previous study, while it hasn’t been reported on the research about diabetic nephropathy. The present study was performed to investigate the pathogenesis of IGF-1 and PI3K/Akt signal pathway in diabetic nephro- pathy and observe whether catapol could protect renal function through regulating the expression of IGF-1. Moreover, it could provide a clue of traditional Chinese medicine in clinical application.
Methods Male Sprague-Dawley (SD) rats were randomly divided into three groups: normal control group (NC), diabetic control group (DM) and diabetic group treated with catapol (DT) including 12 rats for each group. The diabetic rat models were induced by intraperitoneal injection of streptozotocin (STZ) (50mg/kg). Since 8th week point, the rats of DT group were administered with catapol (5mg/kg) by intraperitoneal injection once daily for 2 weeks, while the other two groups were injected with equal volume of normal saline. All rats were in metablic cage to collect 24h urine samples for urinary albumin excretion (UAE), urine microalbumin (MA), urine creatinine (Cre) testing and MA/Cre calculating at the 8th and 10th week. The next day after ten-week, before sacrificed, rats’blood was sampling from heart for measuring HbA1c, BUN, Scr levels and Ccr calculating. Then the kidneys were removed quickly for measuring relative kidney weight (KW/BW). The left kidney was dyed by HE, PAS and PASM to observe pathologic morphology and detected the expression of IGF-1 and Akt1 by immunohistochemistry. While the right kidney was used to detect the change of IGF-1 and Akt at both the levels of mRNA and protein.
Results
1. Body weight (g), Blood glucose (mmol/L) and HbA1C (%): At the 10th week, mean weights of DM group (266.77±55.47) and DT group (279.50±43.56) were significantly lower (P <0.001) than the NC group (356.22±50.73); Blood glucose and HbA1C of DM (25.37±3.56&5.92±0.72) and DT group (23.54±8.70&6.12±0.07) were significantly higher (P<0.001) than that of NC group, while the blood glucose and HbA1C were normal in the NC group (5.72±1.22&3.30±0.10), but there was no significant difference (P >0.05) between DM and DT group on body weight, blood glucose and HbA1C.
2. Renal function and relative kidney weight: At the 10th week, the values of MA/Cre (mg/mmol) for DM group (17.35±3.51) and DT group (15.54±3.57) were markedly higher (P<0.001) than that of NC group (3.79±1.02); The levels of 24h urinary albumin excretion (mg/24h) for DM group (1.00±0.21) and DT group (0.81±0.34) were significant higher (P<0.05) than that of NC group (0.21±0.06); The relative kidney weight (%) in DM (6.09±0.91) and DT group (5.93±0.69) were significantly higher (P<0.001) than that in NC group (4.03±0.50). The data of DT group was lower than that of DM group, but there was no significant difference (P>0.05). Scr and Ccr levels were normal in each group (P >0.05).
3. Histopathological assessment: In PAS and PASM dyed slides, diabetic non-treated rats showed proliferation of mesangial cells, with expansion of mesangial matrix, as well as thickening of ECM. Classic change in DN such as sclerotic nodule formation in glomeruli was observed. But the above pathology change obviously reduced in DT group.
4. RT-PCR: In renal tissue, the expression of IGF-1 mRNA in DM group (0.57±0.17) increased significantly (P <0.05) than NC group (0.38±0.11) while there was no significant difference (P >0.05) between the DT (0.42±0.21) and NC group. The expression of Akt1 mRNA of DM (1.02±0.58) and DT group (0.89±0.34) increased significantly (P <0.05) than NC group (0.56±0.19), while the level of DT group was significantly lower (P<0.05) than DM group.
5. Western blotting: Western blotting showed the activity of p-Akt was increased (P <0.001) in DM group (0.86±0.08) and DT group (0.65±0.06) compared with that of NC group (0.42±0.11), and it was markedly down-regulated (P <0.05) in DT group than DM group.
6. Immunohistochemistry: In all three groups, renal glomerulus, proximal convoluted tubule and collecting tube were showing positive localization. The average optical density (AOD) of IGF-1 in DM group (10.35±0.73) was significantly increased (P <0.001) than NC group(4.81±0.62), but the AOD of DT group (5.63±1.77) was markedly lower (P<0.001) than DM group. The AOD of Akt1 in DM (15.49±2.33) and DT group (9.20±1.27) were both higher (P <0.001) than NC group (3.01±1.13), while the AOD of DT was lower (P <0.001) than DM group.
Conclution
1. The renal function was gradually impaired and the pathology of glomerular basement membrane thickening and extracellular matrix proliferation were observed at the 8th week after the onset of diabetes.
2. The over-expression of IGF-1 in diabtic rats played a major role in DN, at least in part, by activation of PI3K/Akt signal pathway.
3. Catapal could down-regulate IGF-1 and Akt activities and reduce the pathology changes in diabetic kidney to a certain extent, however there was no exact improvement in 24h urinary albumin excretion, MA/Cre and renal fuction values.
引文
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8.王小年,李志新. 2型糖尿病患者血浆IGF-1水平与心脑大血管并发症的关系. Med J CASC, 2003, 5(2):24-25.
9.元勇,李建军,徐美华等.美国糖尿病学会关于糖尿病视网膜病变的报道.中国糖尿病杂志, 2007, 15(7):440-441.
10. Layton CJ, Becker S, Osborne N, et al. The effect of insulin and glucose levels on retinal glial cell activation and pigment epithelium derived fibroblast growth factor-2. Molecular Vision. 2006, 12:43-54.
11.朱清,徐济良,顾锦华等.糖尿病早期大鼠背根神经节IGF-1与GAP-43mRNA的表达. Journal of Nantong University (Medical Sciences), 2007, 27(2):95-100.
12. Oemar BS, Foeller HG, Anandant LH, et al. Regulation of insulin-like growth factor 1 receptors in diabetic mesangial cells. The Journal of Biological Chemi- stry, 2000, 266(4):2369-2373.
13. Horney MJ, Shirley DW, Kurtz DT, et al. Elevated glucose increases mesangial cell sensitivity to insulin-like growth factor 1. AJP-Renal Physiology, 2006, 274: 1045-1053.
14. Lam S, Geest RN, Verhagen NA, et al. Connective tissue growth factor and IGF-1 are produced by human renal fibroblasts and cooperate in the induction of collagen production by high glucose. Diabetes, 2003, 52:2975-2938.
15. Lupia E, Elliot SJ, Lenz O, et al. IGF-1 decreases collagen degration in diatetic NOD mesangial cells. Diabetes, 2000, 48:1638-1644.
16. Maeda M, Yabuki A, Suzuki S, et al. Renal lesions in spontaneous insulin- dependent diabetes mellitus in the nonbese diabetic mouse: acute phase of diabetes. Vet Pathol, 2003, 40:187-195.
17. Raz I, Wexler I, Weiss O, et al. Role of insulin and the IGF system in renal hypertrophy in diabetic psammomys obesus(sand rat). Nephrol Dia Transplant, 2003, 18:1293-1298.
18. Cummings EA, Sochett EB, Dekker MG, et al. Contribution of growth hormone and IGF-1 to early diabetic nephropathy in type 1 diabetes. Diabetes, 2001, 49: 1961-1968.
19.张咏言,王学清,刘聪等. 2型糖尿病血胰岛素样生长因子-1水平与糖尿病肾病的关系.临床荟萃, 2000, 15(11):485-486.
20.张燕,许炯,杨卫华. 2型糖尿病患者血IGF-1与TNF-α相关性评估.天津医科大学学报, 2004, 10(2):288-289.
21. Singh LP, Jiang Y, Cheng DW. Proteomic identification of 14-3-3ζas an adapter for IGF-1 and Akt/GSK-3βsignaling and suvival of renal mesangial cells. Int. J. Biol. Sci, 2007, 3(1):27-39.
22. Jiang B, Liu JH, Bao YM, et al. Catalpol inhibits apoptosis in hydrogen peroxide- induced PC12 cells by preventing cytochrome c release and inactivating of caspase cascade. Toxicon, 2004, 43:53-59.
23. Goruppi S, Bonventre JV, Kyriakis JM, et al. Signaling pathways and late-onset gene induction associated with renal mesangial cell hypertuophy. The EMBO Journal, 2002, 21(20):5427-5436.
24. Povsic TJ, Kohout TA, Lefkowitz RJ.β-Arrestin 1 mediates insulin-like growth factor(IGF-1) activation of phosphatidylinositol-3-kinase(PI3K) and anti- apoptosis. The Journal of Biological Chemistey, 2003, 278(51):51334-51339.
25. Tack I, Elliot SJ, Potier M, et al. Autocrine activation if the IGF-1 signalingpathway in mesangialcells isolated from diabetic NOD mice. Diabetes, 2002, 51:182-188.
26. Akahori H, Ota T, Torita M, et al. Tranilast prevents the progression of experimental diabetic nephropathy through suppression if enhanced extrcellular matrix gene expression. The Journal of Pharmacology and Experimental Ther- apertics, 2005, 314(2):514-521.
27. Bach LA, Dean R, Youssef S, et al. Aminoguanidine ameliorates changes in the IGF system in experimental diabetic nephropathy. Nephrol Dial Transplant, 2000, 15:347-354.
28. Ruggenenti P, Flores C, Aros C, et al. Renal and metabolic effects of insulin lispro in type 2 diabetic subjects with ovent nephropathy. Diabetes Care, 2003, 26(2):502-509.
29. Fan YP, Weiss RH. Exogenous attenuation of P21wnf1/cop1 decreases mesangial cell hyperglycemia and IGF-1. J Am Soc Nephrol, 2004, 15:575-584.
1. Wolf G. Growth factor and the development of diabetic nephropathy.Curr Diab Rep, 2003, 3(6):485-490.
2. Cantley LC. The phosphoinositide3-kinase pathway. Science, 2002, 296(5573):1655-1657.
3. Li X, Teitell MA, Lawson DA, et al. Progression of prostate cancer by synergy of AKT with genetric and nongenotropic actions of the androgen receptor. PNAS, 2006, 103(20):7789-7794.
4. Dearth RK, Cui XJ, Kim HJ, et al. Mammary tumorigenesis and mtastasis caused by overexpression of insulin receptor substrate(IRS-1) or IRS-2. Molecular and Cellular Biology, 2006, 26(24):9302-9314.
5. Singh LP, Jiang Y, Cheng DW. Proteomic identification of 14-3-3ζas an adapter for IGF-I and Akt/GSK-3βsignaling and survivial of renal mesangial cells. International Journal of Biological Sciences, 2007, 3(1):27-39.
6. Li DQ, Duan YL, Bao YM, et al. Neuroprotection of catalpol in transient global ischemia in gerbils. Neuroscience Research, 2004, 50:169-177.
7. Yoshida M, Kimura H, Kyuki K, et al. Effect of combined vitamin E and insulin administration on renal damage in diabetc rats fed a high cholesterol diet. Biol. Pharm. Bull. 2005, 28(11):2080-2086.
8. Maeda M, Yabuki A, Suzuki S, et al. Renal lesions in spontaneous insulin- dependent diabetes mellitus in the nonobese diabetic mouse:acute phase of diabetes. Vet Pathal, 2003, 40:187-195.
9. Landau D, Israel E, Rivkis I, et al. The effect of growth hormone on the development of diabetic kidney disease in rats. Nephrol Dial Transplant, 2003, 18:694-702.
10. Oemar BS, Foeller HG, Auandant LH, et al. Regulation of insulin-like growth factor 1 receptors in diabetic mesangial cells. The Journal of Biological Chemistry, 2000, 266(4):2369-2373.
11. Lam S, Geest RN, Verhager NA, et al. Connective tissue growth factor and IGF-1 are produced by human renal fibroblasts and cooperate in the induction of collagen production by high glucose. Diabetes, 2003, 52:2975-2938.
12. Ristic VC, Schrijvers BF, Vliet AK, et al. Kidney growth in normal and diabetic mice is not affected by human insulin-like growth factor binding protein-1administration. Exp Biol Med, 2005, 230:135-143.
13. Landan D, Chin E, Bondy C, et al. Expression of insulin-like growth factor binding proteins in the rat kidney: effects of long-term diabetes. Endocrinology, 1995, 136(5):1835-1842.
14. Kang BP, Urbnas A, Baddoo A, et al. IGF-1 inhibits the mitochondrial apoptosis program in mesangial cells exposed to high glucose. AJP-Renal, 2003, 285: 1013-1024.
15. Bridyewater DJ, Ho J, Sauro V, et al. Insulin-like growth factors inhibit podocyte apoptosis though the PI3K kinase pathway. Kidney International, 2005, 67: 1308-1314.
16. Singh LP, Jiang Y, Cheng DW. Proteomic identification of 14-3-3ζas an adapter for IGF-1 and Akt/GSK-3βsignaling and suvival of renal mesangial cells. Int. J. Biol. Sci, 2007 3(1):27-39.
17. Sheikh SS, Domin J, Tomitchong P, et al. Topographical exprssion of classⅠA and classⅡphosphoinositide 3-kinase enzymes in normal human tissues is consistent with a role in differentiation. BMC Clinical Pathology, 2003, 3(4): 1- 14.
18. Yang ZZ, Tschopp O, Bruder E, et al. Dosage-dependent effects of Akt1/protein kinase Bα(PKBα) and Akt3/PKBγon thymus, skin, and cardiovascular and nervous system development in mice. Molecular and Cellular Biology, 2005, 25(23):10407-10418.
19.张汝学,周金黄,贾正平等.地黄寡糖抗糖尿病药理作用及机制研究回顾.中药药理与临床. 2003,19(20):48-49.
20. Li DQ , Duan YL, Bao YM, et al. Neuroprotection of catalpol in transient global ischemia in gerbils. Neuroscience Research, 2004, 50:169-177.
21. Li DQ, Bao YM, Zhao JJ, et al. Neuroprotective properties of catopol in transient global cerebral ischemal in gerbils: dose-response, therapeutic time-window and long-term efficacy. Brain Research, 2004, 1029:179-185.
2. Salvatori R. Growth hormone and IGF-1. Reviews in Endocrine & Metabolic Disorders, 2004, 5:15-23.
3. Zaka M, Rafi MA, Rao HZ, et al. Insulin-like growth factor-1 provides protection against psychosine-induced apoptosis in cultured mouse oligodendrocyte pro- genitor cells using primarily the PI3K/Akt pathway. Molecular and Cellular Neuroscience, 2005, 30:398-407.
4. Bai HZ, Pollman MJ, Inishi Y, et al. Regulation of vascular smooth muscle cell apoptosis ; modulation of Bad by a phosphatidylinositol 3-kinase-dependent pathway. Circ. Res, 2006, 85:229-237.
5. Oliver SE, Gunnell D, Donovan J, et al. Screen-detected prostate cancer and the insulin-like growth factor axis: results of a population-based case-control study. Int. J. Cancer, 2004, 108:887-892.
6. Haffner MC, Petridou B, Peyrat JP, et al. Favorable prognostic value of SOCS2 and IGF-1 in breat cancer. BMC Cancer, 2007, 7:136-145.
7. Celil AB, Campbell PG. BMP-2 and insulin-like growth factor-1 mediate osterix (Osx) expression in human mesenchymal stem cells via the MAPK and protein kinase D signaling pathways. The Journal of Biological Chemistry, 2005, 280(36): 31353-31359.
8.王小年,李志新. 2型糖尿病患者血浆IGF-1水平与心脑大血管并发症的关系. Med J CASC, 2003, 5(2):24-25.
9.元勇,李建军,徐美华等.美国糖尿病学会关于糖尿病视网膜病变的报道.中国糖尿病杂志, 2007, 15(7):440-441.
10. Layton CJ, Becker S, Osborne N, et al. The effect of insulin and glucose levels on retinal glial cell activation and pigment epithelium derived fibroblast growth factor-2. Molecular Vision. 2006, 12:43-54.
11.朱清,徐济良,顾锦华等.糖尿病早期大鼠背根神经节IGF-1与GAP-43mRNA的表达. Journal of Nantong University (Medical Sciences), 2007, 27(2):95-100.
12. Oemar BS, Foeller HG, Anandant LH, et al. Regulation of insulin-like growth factor 1 receptors in diabetic mesangial cells. The Journal of Biological Chemi- stry, 2000, 266(4):2369-2373.
13. Horney MJ, Shirley DW, Kurtz DT, et al. Elevated glucose increases mesangial cell sensitivity to insulin-like growth factor 1. AJP-Renal Physiology, 2006, 274: 1045-1053.
14. Lam S, Geest RN, Verhagen NA, et al. Connective tissue growth factor and IGF-1 are produced by human renal fibroblasts and cooperate in the induction of collagen production by high glucose. Diabetes, 2003, 52:2975-2938.
15. Lupia E, Elliot SJ, Lenz O, et al. IGF-1 decreases collagen degration in diatetic NOD mesangial cells. Diabetes, 2000, 48:1638-1644.
16. Maeda M, Yabuki A, Suzuki S, et al. Renal lesions in spontaneous insulin- dependent diabetes mellitus in the nonbese diabetic mouse: acute phase of diabetes. Vet Pathol, 2003, 40:187-195.
17. Raz I, Wexler I, Weiss O, et al. Role of insulin and the IGF system in renal hypertrophy in diabetic psammomys obesus(sand rat). Nephrol Dia Transplant, 2003, 18:1293-1298.
18. Cummings EA, Sochett EB, Dekker MG, et al. Contribution of growth hormone and IGF-1 to early diabetic nephropathy in type 1 diabetes. Diabetes, 2001, 49: 1961-1968.
19.张咏言,王学清,刘聪等. 2型糖尿病血胰岛素样生长因子-1水平与糖尿病肾病的关系.临床荟萃, 2000, 15(11):485-486.
20.张燕,许炯,杨卫华. 2型糖尿病患者血IGF-1与TNF-α相关性评估.天津医科大学学报, 2004, 10(2):288-289.
21. Singh LP, Jiang Y, Cheng DW. Proteomic identification of 14-3-3ζas an adapter for IGF-1 and Akt/GSK-3βsignaling and suvival of renal mesangial cells. Int. J. Biol. Sci, 2007, 3(1):27-39.
22. Jiang B, Liu JH, Bao YM, et al. Catalpol inhibits apoptosis in hydrogen peroxide- induced PC12 cells by preventing cytochrome c release and inactivating of caspase cascade. Toxicon, 2004, 43:53-59.
23. Goruppi S, Bonventre JV, Kyriakis JM, et al. Signaling pathways and late-onset gene induction associated with renal mesangial cell hypertuophy. The EMBO Journal, 2002, 21(20):5427-5436.
24. Povsic TJ, Kohout TA, Lefkowitz RJ.β-Arrestin 1 mediates insulin-like growth factor(IGF-1) activation of phosphatidylinositol-3-kinase(PI3K) and anti- apoptosis. The Journal of Biological Chemistey, 2003, 278(51):51334-51339.
25. Tack I, Elliot SJ, Potier M, et al. Autocrine activation if the IGF-1 signalingpathway in mesangialcells isolated from diabetic NOD mice. Diabetes, 2002, 51:182-188.
26. Akahori H, Ota T, Torita M, et al. Tranilast prevents the progression of experimental diabetic nephropathy through suppression if enhanced extrcellular matrix gene expression. The Journal of Pharmacology and Experimental Ther- apertics, 2005, 314(2):514-521.
27. Bach LA, Dean R, Youssef S, et al. Aminoguanidine ameliorates changes in the IGF system in experimental diabetic nephropathy. Nephrol Dial Transplant, 2000, 15:347-354.
28. Ruggenenti P, Flores C, Aros C, et al. Renal and metabolic effects of insulin lispro in type 2 diabetic subjects with ovent nephropathy. Diabetes Care, 2003, 26(2):502-509.
29. Fan YP, Weiss RH. Exogenous attenuation of P21wnf1/cop1 decreases mesangial cell hyperglycemia and IGF-1. J Am Soc Nephrol, 2004, 15:575-584.
1. Wolf G. Growth factor and the development of diabetic nephropathy.Curr Diab Rep, 2003, 3(6):485-490.
2. Cantley LC. The phosphoinositide3-kinase pathway. Science, 2002, 296(5573):1655-1657.
3. Li X, Teitell MA, Lawson DA, et al. Progression of prostate cancer by synergy of AKT with genetric and nongenotropic actions of the androgen receptor. PNAS, 2006, 103(20):7789-7794.
4. Dearth RK, Cui XJ, Kim HJ, et al. Mammary tumorigenesis and mtastasis caused by overexpression of insulin receptor substrate(IRS-1) or IRS-2. Molecular and Cellular Biology, 2006, 26(24):9302-9314.
5. Singh LP, Jiang Y, Cheng DW. Proteomic identification of 14-3-3ζas an adapter for IGF-I and Akt/GSK-3βsignaling and survivial of renal mesangial cells. International Journal of Biological Sciences, 2007, 3(1):27-39.
6. Li DQ, Duan YL, Bao YM, et al. Neuroprotection of catalpol in transient global ischemia in gerbils. Neuroscience Research, 2004, 50:169-177.
7. Yoshida M, Kimura H, Kyuki K, et al. Effect of combined vitamin E and insulin administration on renal damage in diabetc rats fed a high cholesterol diet. Biol. Pharm. Bull. 2005, 28(11):2080-2086.
8. Maeda M, Yabuki A, Suzuki S, et al. Renal lesions in spontaneous insulin- dependent diabetes mellitus in the nonobese diabetic mouse:acute phase of diabetes. Vet Pathal, 2003, 40:187-195.
9. Landau D, Israel E, Rivkis I, et al. The effect of growth hormone on the development of diabetic kidney disease in rats. Nephrol Dial Transplant, 2003, 18:694-702.
10. Oemar BS, Foeller HG, Auandant LH, et al. Regulation of insulin-like growth factor 1 receptors in diabetic mesangial cells. The Journal of Biological Chemistry, 2000, 266(4):2369-2373.
11. Lam S, Geest RN, Verhager NA, et al. Connective tissue growth factor and IGF-1 are produced by human renal fibroblasts and cooperate in the induction of collagen production by high glucose. Diabetes, 2003, 52:2975-2938.
12. Ristic VC, Schrijvers BF, Vliet AK, et al. Kidney growth in normal and diabetic mice is not affected by human insulin-like growth factor binding protein-1administration. Exp Biol Med, 2005, 230:135-143.
13. Landan D, Chin E, Bondy C, et al. Expression of insulin-like growth factor binding proteins in the rat kidney: effects of long-term diabetes. Endocrinology, 1995, 136(5):1835-1842.
14. Kang BP, Urbnas A, Baddoo A, et al. IGF-1 inhibits the mitochondrial apoptosis program in mesangial cells exposed to high glucose. AJP-Renal, 2003, 285: 1013-1024.
15. Bridyewater DJ, Ho J, Sauro V, et al. Insulin-like growth factors inhibit podocyte apoptosis though the PI3K kinase pathway. Kidney International, 2005, 67: 1308-1314.
16. Singh LP, Jiang Y, Cheng DW. Proteomic identification of 14-3-3ζas an adapter for IGF-1 and Akt/GSK-3βsignaling and suvival of renal mesangial cells. Int. J. Biol. Sci, 2007 3(1):27-39.
17. Sheikh SS, Domin J, Tomitchong P, et al. Topographical exprssion of classⅠA and classⅡphosphoinositide 3-kinase enzymes in normal human tissues is consistent with a role in differentiation. BMC Clinical Pathology, 2003, 3(4): 1- 14.
18. Yang ZZ, Tschopp O, Bruder E, et al. Dosage-dependent effects of Akt1/protein kinase Bα(PKBα) and Akt3/PKBγon thymus, skin, and cardiovascular and nervous system development in mice. Molecular and Cellular Biology, 2005, 25(23):10407-10418.
19.张汝学,周金黄,贾正平等.地黄寡糖抗糖尿病药理作用及机制研究回顾.中药药理与临床. 2003,19(20):48-49.
20. Li DQ , Duan YL, Bao YM, et al. Neuroprotection of catalpol in transient global ischemia in gerbils. Neuroscience Research, 2004, 50:169-177.
21. Li DQ, Bao YM, Zhao JJ, et al. Neuroprotective properties of catopol in transient global cerebral ischemal in gerbils: dose-response, therapeutic time-window and long-term efficacy. Brain Research, 2004, 1029:179-185.
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