β-酪啡肽-7对STZ诱导的糖尿病肾病大鼠肾损伤的保护作用及其机制研究
|
摘要
本研究选用健康雄性SD大鼠,以链脲佐菌素(streptozotocin, STZ)诱导糖尿病大鼠肾病模型,研究乳源活性肽β-酪啡肽-7(β-casomorphin-7, p-CM-7)对糖尿病肾病大鼠肾脏功能和组织学变化、肾脏氧化应激、肾小管上皮-肌成纤维细胞转分化(TEMT)及肾脏肾素-血管紧张素系统(RAS)的影响；细胞水平上揭示AngⅡ作用对大鼠肾小管上皮细胞的影响,并深入研究和阐明β-CM-7增强大鼠抵抗肾脏损伤的作用机制。研究包括四个部分：
1β-酪啡肽-7对糖尿病肾病大鼠肾损伤的保护作用
研究β-CM-7对链脲佐菌素(STZ)诱导的试验性糖尿病肾病大鼠肾脏损伤的保护作用。40只SD大鼠随机取8只作为正常对照组(Control group),其余大鼠腹腔注射STZ(60mg/kg体重)溶液制造糖尿病模型。造模成功大鼠分为模型组(Model group)和β-酪啡肽-7组(β-CM-7group)。β-CM-7组大鼠每天灌胃7.5×10-6mol/kg体重的β-CM-7,其它两组大鼠分别灌胃等量的生理盐水。观察大鼠每天的饮水、采食及体重等变化,每5天测定空腹血糖1次。连续灌胃30天后处死所有大鼠,取血清、肾脏组织等,每组随机选取8只进行如下试验：1)测定大鼠尿糖、尿蛋白、肾功能相关指标和血清中胰岛素及胰高血糖素的含量；2)HE、Masson及天狼星红(Sirius red)染色分析大鼠肾脏组织病理变化及肾脏胶原纤维的变化；3)定量分析大鼠肾脏Ⅰ型胶原蛋白(collagenⅠ)和Ⅳ型胶原蛋白(collagenⅣ)的mRNA和蛋白表达变化。结果：1)32只大鼠用于造模,27只造模成功,造模成模率84%。试验期间,模型对照组大鼠出现多饮、多食、体重下降等临床症状,血糖一直维持在16.7mmol/L以上,血清中胰岛素含量显著降低(P<0.05),胰高血糖素含量显著升高(P<0.05)。与模型组大鼠比较,β-CM-7组大鼠的采食量、饮水量和空腹血糖值均有降低,体重略有升高；2)成模30天后,模型组大鼠尿糖、尿蛋白,血清肌酐、尿素氮含量均明显高于对照组(P<0.05),肾脏指数明显增高(P<0.01),病理组织学变化明显；β-CM-7干预后,上述指标水平均有降低,组织损伤减轻；3)模型组大鼠在肾小球和肾小管间质出现了大量的胶原纤维沉积,肾脏中Ⅰ型胶原蛋白和Ⅳ型胶原蛋白的mRNA和蛋白表达均显著高于对照组大鼠(P<0.05)。与模型组大鼠比较,β-CM-7组大鼠胶原纤维沉积明显减少。结论：腹腔注射STZ可用于诱导糖尿病大鼠肾病模型,首先该模型大鼠表现多饮、多食、体重下降。成模30天后,表现为糖尿,蛋白尿,’肾脏肥大、肾功能受损及肾脏纤维化等糖尿病肾病特征性病变；β-CM-7对STZ诱导的糖尿病肾病大鼠肾损伤有一定的保护作用。
2β-CM-7对糖尿病肾病大鼠肾损伤的机制初探
上一章的研究发现p-CM-7具有缓解糖尿病肾病大鼠肾脏功能损伤及组织纤维化的作用,对糖尿病肾损伤具有一定的保护作用。本章将从肾脏氧化应激和肾小管上皮-肌成纤维细胞转分化(Tubular Epithelial-Myofibroblas transdifferentiation, TEMT)两个方面探讨其可能的机制。试验大鼠及处理同第一章。取第一章各组大鼠肾脏进行如下试验：1)生化法测定肾脏组织中MDA和H202含量,SOD, GPx (?)勺酶活及T-AOC;2) Real-time PCR定量测定大鼠肾脏组织中α-平滑肌肌动蛋白(α-SMA),E-钙粘蛋白(E-cadherin),波形蛋白(vimentin)和角蛋白19(CK19)的mRNA表达水平Western-blot和免疫组化法检测α-SMA和E-cadherin蛋白的表达与分布。结果：1)模型组大鼠肾脏组织中抗氧化酶SOD和GPx活性均显著低于对照组(P<0.01), MDA含量显著升高(P<0.01)；与模型组比较,β-CM-7组大鼠肾脏组织中SOD和GPx酶活力均显著升高(P<0.01),MDA含量降低(P<0.05)；T-AOC和H2O2介于对照组和模型组之间,无统计学意义(P>0.05)；2)与对照组大鼠相比,模型组大鼠肾脏α-SMA(P<0.01)和波形蛋白(P<0.05)mRNA表达水平显著升高,E-cadherin (P<0.05)和CK19(P<0.01) mRNA的表达水平显著降低。与模型组大鼠比较,β-CM-7显著降低了α-SMA和波形蛋白mRNA表达水平(P<0.05),升高E-cadherin (P<0.05)和CK19(P<0.01)mRNA表达水平；3)免疫组化结果显示模型组大鼠E-cadherin在肾小管中的分布明显减少,α-SMA分布有所增多,肾小管出现了转分化。β-CM-7拮抗了这种变化,两种蛋白的蛋白表达结果与mRNA表达结果一致。结论：β-CM-7能够抑制糖尿病肾病大鼠肾脏的氧化应激和肾小管上皮-肌成纤维细胞的转分化。增强抗氧化能力,抑制TEMT可能是β-CM-7保护糖尿病肾病大鼠肾损伤的机制之一
3β-CM-7对糖尿病肾病大鼠肾局部肾素-血管紧张素系统的影响
上一章的结果提示β-CM-7保护糖尿病肾病大鼠肾损伤的作用可能与其增强肾脏抗氧化能力,抑制肾小管上皮-肌成纤维细胞的转分化有关。本章将从肾素-血管紧张素系统(Renin-angiotensin system, RAS)途径进一步探讨3-CM-7保护糖尿病肾病大鼠肾损伤的新的机制。试验大鼠及处理同第一章。取第一章各组大鼠肾脏进行如下试验：放射免疫法(RIA)测定大鼠肾脏组织中AngⅡ的含量；Real-time PCR检测大鼠肾脏组织中ACE、AT1、ACE2和MAS的mRNA表达；Western blot检测大鼠肾脏组织中ACE和ACE2蛋白的表达。结果：1)与对照组大鼠比较,模型组大鼠肾脏组织中AngⅡ的含量极显著升高(P<0.01)；灌胃β-CM-7后降低了肾脏局部AngⅡ (P=0.035)的含量,但仍高于对照组；2)与对照组比较,模型组大鼠肾脏组织中ACE2mRNA及蛋白的表达均显著降低(P<0.05),ACE mRNA和蛋白及AT1受体mRNA的表达显著升高(P<0.05), MAS mRNA表达略有降低,差异不显著(P=0.09)。β-酪啡肽-7显著上调了ACE2mRNA及蛋白的表达(P<0.05),ACE mRNA和蛋白及AT1受体的mRNA表达均降低(P<0.05), MAS mRNA的表达水平略有升高(P=0.07)；3)模型组大鼠肾脏中ACE/ACE2mRNA和ACE蛋白/ACE2蛋白的比值均显著高于对照组(P<0.01)；灌胃β-CM-7后,两比值均显著降低(P<0.05)。结论：糖尿病肾病时,肾脏局部RAS处于激活状态,ACE-AngⅡ-AT1轴活性占优势,高水平的AngⅡ参与了肾脏的损伤及纤维化。β-CM-7能够通过升高ACE2的表达,降低AngⅡ的高水平和AT1受体的表达,抑制RAS的过度激活,抑制糖尿病肾病大鼠的肾损伤。AngⅡ是糖尿病肾病大鼠肾损伤的关键因素,也可能是β-CM-7抑制糖尿病肾病大鼠肾损伤的关键通路。
4β-CM-7对AngⅡ刺激的肾小管上皮细胞氧化应激及转分化影响的细胞学研究
在细胞水平上深入探讨β-CM-7对AngⅡ诱导的细胞氧化应激及肾小管上皮-肌成纤维细胞转分化(TEMT)(?)(?)影响及其机制。方法采用DMEM培养基对NRK-52E肾小管上皮细胞进行体外培养,细胞分为对照组(Control group)、AngⅡ处理组(AngⅡ group)、β-酪啡肽-7干预组(β-CM-7group)及AT1受体阻断剂组(ARB group)。AngⅡ处理组于培养基中添加1nM的AngⅡ,β-CM-7干预组于培养基中加入1nM的AngⅡ及10-5M的β-CM-7, AT1受体阻断剂组于培养基中添加1nM的AngⅡ及10-5mol/L洛沙坦,对照组等量DMEM培养液；处理72h后,收集细胞及上清。生化法检测肾小管上皮细胞中氧化应激及抗氧化应激指标；Real-time PCR检测肾小管上皮细胞转分化、RAS主要因子及转化生长因子-β1(Transforming growth factor-β1, TGF-β1)等相关蛋白的mRNA表达；Western-blot及免疫荧光检测细胞转分化、RAS等相关蛋白的表达；RIA及ELISA分别检测细胞上清中AngⅡ及TGF-β1的含量。结果：1)AngⅡ处理NRK-52E肾小管上皮细胞,其中ROS及MDA的含量显著升高(P<0.01),SOD及GPx的活性显著降低(P<0.01),细胞发生氧化应激；β-CM-7干预可显著降低ROS及MDA的含量,升高SOD及GPx的活性；2) AngⅡ处理能够上调NRK-52细胞中α-SMA的mRNA及蛋白表达(P<0.01),下调E-cadherin mRNA及蛋白表达(P<0.01),AT1受体阻断剂可以拮抗这种作用。β-CM-7处理能够显著抑制AngⅡ引起α-SMA及E-cadherin的表达变化；3)AngⅡ处理的NRK-52E细胞中ACE2mRNA及蛋白的表达显著降低(P<0.05),ACE mRNA(P<0.01)及蛋白(P<0.05)的表达显著升高,TGF-β1的含量显著升高；β-CM-7干预显著上调了细胞中ACE2mRNA及蛋白的表达,下调ACE mRNA及蛋白的表达,AngⅡ及TGF-β1的含量均降低。结论：AngⅡ可以通过AT1受体,升高TGF-β1,介导NRK-52E细胞氧化应激及转分化; β-CM-7能够有效抑制AngⅡ介导的肾小管上皮细胞的氧化应激及转分化；其机制是：升高ACE2的表达,抑制ACE的表达,降低AngⅡ及TGF-β1的含量
In this study, effects of beta-casomorphin-7on renal funtion, morphological changes, oxidative stress, tubular epithelial-myofibroblast transdifferentiation (TEMT) and renin-angiotensin system (RAS) were first evaluated on the rats with diabetic nephropathy which were induced by STZ. The damage responses of AngⅡ on renal tubular epithelial cells were detected in vitro and studied the mechanism of beta-casomorphin-7on renal injury of rats. The research included four parts:
1The protective effect of β-casomorphin-7on renal injury on rats with diabetic nephropathy
This study was designed to investigate the protective effect of P-casomorphin-7on renal injury of streptozotocin-induced diabetic rats. Eight SD rats were selected as the control group in40rats,32rats were induced by intraperitoneal injection of STZ (60mg/kg body weight) to make the diabetic model. The diabetic rats were divided into model group which were given intragastric administration of saline and β-casomorphins-7group (β-CM-7group) which were given intragastric administration of7.5×10-6mol/kg body weight β-casomorphin-7. The food intake, water intake and the body weight were measured every day. The fasting blood glucose was measured every5days. All rats were sacrificed after30days of feeding with or without β-casomorphin-7, the serum and the kidney were collected and8rats were selected from every group for the following experiments:1) The urine glucose, urine protein, renal function, serum insulin and glucogan were detected.2) The pathological and fibrosis of kidney were detected by HE, MASSON and Sirius red.3) The mRNA and protein expression of type Ⅰ and IVcollagen in the kidney of rats were detected. Results:1)27rats were successfully induced into diabetic model in32rats and successful rate is84%. During the experiment, the water intake and food intake were increased significantly, the body weight was decreased significantly, the fasting blood glucose had been higher than16.7mmol/L during the experiment, the content of insulin was decreased (P<0.05) and the content of glucagon (P<0.05) was increased in the rats of model group. Compared with the rats of model group, β-CM-7decreased the food intake, water intake and fasting blood glucose, increased the body weight.2) After30days treatment, the urine glucose, urine protein, serum creatinine, blood urea nitrogen (P<0.05) and renal index (P<0.01) in the rats of model group were significantly increased and the kidney had obvious histopathological changes, β-casomorphin-7decreased the above index and renal histopathological changes.3) There were excessive deposition of collagen fibers in glomerulus and tubulointerstitial in the rats of model group, the mRNA and protein of type Ⅰ and Ⅳ collagen were significantly increased in the kidney of model group (P<0.05), β-casomorphin-7reduced deposition of collagen fibers in kidney of diabetic rats. Conclusions:Intraperitoneal injection of STZ could been used for inducing the diabetic nephropathy which first performed that more water intake, more food intake and loss of weight, and after30days the rats in model group performed glycosuria, proteinuria, renal hypertrophy, renal dysfuction and renal fibrosis. β-casomorphin-7had a protective effect on the kidney of rats with diabetic nephropathy induced by STZ.
2The possible mechanism of β-CM-7on renal injury of rats with diabetic nephropathy
We had found that β-CM-7had the protective effect on renal injury of rats with diabetic nephropathy in the previous experiment and this study explored the possible mechanism from the oxidative stress and renal tubular epithelial-myofibroblast transdifferentiation (TEMT). All rats were treated the same as the first chapter and the kidney were collected for the following experiments:1) The contents of MDA and H2O2, the SOD, GPx and T-AOC were determined by biochemical assay.2) Expression of α-smooth muscle actin (α-SMA), E-cadherin, vimentin and cytokeratinl9(CK19) mRNA in the rats were detected by real-time PCR. The protein expression and distribution of α-SMA and E-cadherin were detected by Western-blot and immunohistochemistry. Results:1) The activity of SOD and GPx (P<0.01) were significant lower and the contents of MDA (P<0.01) were significant higher than the control group in the kidney. β-CM-7increased the SOD (P<0.01), GPx (P<0.05), and decreased the MDA (P<0.05) of rats with diabetic nephropathy. The contents of T-AOC and H2O2in β-CM-7group were between control group and model group, but there is no statistics significance (P>0.05).2) Compared with the control group, the mRNA expression of α-SMA (P<0.01) and vimentin (P<0.05) increased significantly and the expression of E-cadherin (P<0.05) and CK19(P<0.01) mRNA were reduced in model group. β-CM-7reduced the mRNA expression of α-SMA and vimentin (P<0.05), increase the mRNA expression of E-cadherin (P<0.05) and CK19(P<0.01).3) The distribution of E-cadherin was decreased significantly and the α-SMA was increased significantly, renal tubular epithelial cell appeared tubular epithelial-myofibroblast transdifferentiation and β-casomorphin-7antagonized all these changes. The protein expression of E-cadherin and α-SMA were consistent with the expression of mRNA. Conclusion:β-CM-7reduced renal oxidative stress and renal tubular epithelial-myofibroblast transdifferentiation which may be one of the protective mechanisms of β-CM-7on renal injury
3The effect of β-casomorphin-7on RAS of kidney in the rats with diabetic nephropathy
We had found that β-CM-7had the protective effect on renal injury of rats with diabetic nephropathy which was associated with enhancing the antioxidant capacity and inhibiting the renal tubular epithelial-myofibroblast transdifferentiation (TEMT) in the previous experiment. To further explore the new mechanism of beta-casomorphin-7on the renal injury of rats with diabetic nephropathy from the renin-angiotensin system (RAS) in this experiment. All rats were treated the same as the first chapter and the kidney were collected for the following experiments:The content of AngⅡin the kidney of rats were detected by radioimmunoassay. Expression of ACE, AT1, ACE2and MAS mRNA in the kidney of rats were detected by real-time PCR. The protein expression of ACE and ACE2were detected by Western-blqt. Results:1) Compared with control group, content of AngⅡ (P<0.01) was significantly increased in the kidney of rats in model group (P<0.01). β-casomorphin-7decreased content of AngⅡ (P=0.035), but it was also higher than the control group.2) Compared with control group, the expression of ACE2mRNA and protein (P<0.05) was decreased significantly, the expression of ACE protein and mRNA, the AT1mRNA were significantly increased (P<0.05), the expression of MAS mRNA was decreased (P=0.09) which did not have statistical significance in the kidney of model group. β-CM-7could increased the expression of ACE2mRNA and protein(P<0.05), decrease the expression of ACE mRNA and protein, AT1mRNA (P<0.05) and MAS mRNA (P=0.07) in the kidney significantly. The ratio of ACE/ACE2mRNA and ACE/ACE2protein was higher in the kidney of the model group than the control group (P<0.01), β-CM-7decreased the ratio of ACE/ACE2(P<0.05). Conclusion:The RAS were activated in the kidney of rats with diabetic nephropathy and the axis of ACE-AngⅡ-AT1was dominant. The high contents of Angll involved in the renal injury and fibrosis. β-casomorphin-7protected the renal injury and fibrosis of rats with diabetic nephropathy through increasing the expression of ACE2, decreasing the content of AngⅡ and the expression of AT1. AngⅡ was a key factor in renal injury of rats with diabetic nephropathy and it may be a key pathway which β-CM-7protected the renal injury of rats with diabetic nephropathy.
4The effect of β-casomorphin-7on the oxidative stress and TEMT of cells treated with AngⅡ in vitro
The research is further to study the effect and mechanism of β-casomorphin-7on the oxidative stress and tubular epithelial-myofibroblast transdifferentiation (TEMT) of NRK-52E cells treated with AngⅡ. NRK-52E cells were cultured in the DMEM medium and the cells were divided into four group:control group, AngⅡ group, β-CM-7group and AT1receptor blocker group (ARB group). The cells of the AngⅡ group were treated with lnM AngⅡ in DMEM medium, the cells of β-CM-7group were treated with lnM AngⅡ and10-5M β-casomorphin-7in DMEM medium, the cells of ARB group were treated with lnM AngⅡ and10-5M losartan in DMEM medium and the cells of control group were cultured in DMEM medium. All cells were treated for72h and the cells and the culture medium were collected. The index of oxidative stress and antioxidant were detected by biochemical assay. The mRNA expression about TEMT, RAS and TGF-β1were detected by real-time PCR. The protein expression about TEMT and RAS were detected by western-blot and immunofluorescence. The contents of Angll or TGF-β1were detected by radioimmunoassay or ELISA. Result:1) The contents of ROS and MDA were increased (P<0.01) and the SOD and GPx were decreased (P<0.01) in the cells treated with Angll, which increased the oxidative stress of cells. P-CM-7significantly reduced the contents of ROS and MDA, increase the activity of SOD and GPx in the NRK-52E cells treated with Angll, which alleviated the oxidative stress of cells.2) The mRNA and protein expression of α-SMA (P<0.01) was increased and E-cadherin (P<0.01) was decreased in the NRK-52E cells treated with Angll, AT1receptor blocker (ARB) antagonized this changes of α-SMA and E-cadherin and β-CM-7also significantly alleviated the changes of α-SMA and E-cadherin of cells.3) The mRNA and protein expression of ACE was increased (P<0.05), ACE2was decreased (P<0.01&P<0.05)) and the content of TGF-β1was increased in the cells treated with AngⅡ. β-CM-7significantly increase the mRNA and protein expression of ACE2, decrease the mRNA and protein expression of ACE and the contents of AngⅡ and TGF-β1. Conclusion:The oxidative stress and TEMT of NRK-52E cells could be induced by AngⅡ through AT1receptor and TGF-β1. β-CM-7alleviated the oxidative stress and TEMT of NRK-52E cell treated with AngⅡ which is associated with increasing the expression of ACE2, decreasing the expression of ACE and the contents of Ang Ⅱ and TGF-β1.
1β-酪啡肽-7对糖尿病肾病大鼠肾损伤的保护作用
研究β-CM-7对链脲佐菌素(STZ)诱导的试验性糖尿病肾病大鼠肾脏损伤的保护作用。40只SD大鼠随机取8只作为正常对照组(Control group),其余大鼠腹腔注射STZ(60mg/kg体重)溶液制造糖尿病模型。造模成功大鼠分为模型组(Model group)和β-酪啡肽-7组(β-CM-7group)。β-CM-7组大鼠每天灌胃7.5×10-6mol/kg体重的β-CM-7,其它两组大鼠分别灌胃等量的生理盐水。观察大鼠每天的饮水、采食及体重等变化,每5天测定空腹血糖1次。连续灌胃30天后处死所有大鼠,取血清、肾脏组织等,每组随机选取8只进行如下试验：1)测定大鼠尿糖、尿蛋白、肾功能相关指标和血清中胰岛素及胰高血糖素的含量；2)HE、Masson及天狼星红(Sirius red)染色分析大鼠肾脏组织病理变化及肾脏胶原纤维的变化；3)定量分析大鼠肾脏Ⅰ型胶原蛋白(collagenⅠ)和Ⅳ型胶原蛋白(collagenⅣ)的mRNA和蛋白表达变化。结果：1)32只大鼠用于造模,27只造模成功,造模成模率84%。试验期间,模型对照组大鼠出现多饮、多食、体重下降等临床症状,血糖一直维持在16.7mmol/L以上,血清中胰岛素含量显著降低(P<0.05),胰高血糖素含量显著升高(P<0.05)。与模型组大鼠比较,β-CM-7组大鼠的采食量、饮水量和空腹血糖值均有降低,体重略有升高；2)成模30天后,模型组大鼠尿糖、尿蛋白,血清肌酐、尿素氮含量均明显高于对照组(P<0.05),肾脏指数明显增高(P<0.01),病理组织学变化明显；β-CM-7干预后,上述指标水平均有降低,组织损伤减轻；3)模型组大鼠在肾小球和肾小管间质出现了大量的胶原纤维沉积,肾脏中Ⅰ型胶原蛋白和Ⅳ型胶原蛋白的mRNA和蛋白表达均显著高于对照组大鼠(P<0.05)。与模型组大鼠比较,β-CM-7组大鼠胶原纤维沉积明显减少。结论：腹腔注射STZ可用于诱导糖尿病大鼠肾病模型,首先该模型大鼠表现多饮、多食、体重下降。成模30天后,表现为糖尿,蛋白尿,’肾脏肥大、肾功能受损及肾脏纤维化等糖尿病肾病特征性病变；β-CM-7对STZ诱导的糖尿病肾病大鼠肾损伤有一定的保护作用。
2β-CM-7对糖尿病肾病大鼠肾损伤的机制初探
上一章的研究发现p-CM-7具有缓解糖尿病肾病大鼠肾脏功能损伤及组织纤维化的作用,对糖尿病肾损伤具有一定的保护作用。本章将从肾脏氧化应激和肾小管上皮-肌成纤维细胞转分化(Tubular Epithelial-Myofibroblas transdifferentiation, TEMT)两个方面探讨其可能的机制。试验大鼠及处理同第一章。取第一章各组大鼠肾脏进行如下试验：1)生化法测定肾脏组织中MDA和H202含量,SOD, GPx (?)勺酶活及T-AOC;2) Real-time PCR定量测定大鼠肾脏组织中α-平滑肌肌动蛋白(α-SMA),E-钙粘蛋白(E-cadherin),波形蛋白(vimentin)和角蛋白19(CK19)的mRNA表达水平Western-blot和免疫组化法检测α-SMA和E-cadherin蛋白的表达与分布。结果：1)模型组大鼠肾脏组织中抗氧化酶SOD和GPx活性均显著低于对照组(P<0.01), MDA含量显著升高(P<0.01)；与模型组比较,β-CM-7组大鼠肾脏组织中SOD和GPx酶活力均显著升高(P<0.01),MDA含量降低(P<0.05)；T-AOC和H2O2介于对照组和模型组之间,无统计学意义(P>0.05)；2)与对照组大鼠相比,模型组大鼠肾脏α-SMA(P<0.01)和波形蛋白(P<0.05)mRNA表达水平显著升高,E-cadherin (P<0.05)和CK19(P<0.01) mRNA的表达水平显著降低。与模型组大鼠比较,β-CM-7显著降低了α-SMA和波形蛋白mRNA表达水平(P<0.05),升高E-cadherin (P<0.05)和CK19(P<0.01)mRNA表达水平；3)免疫组化结果显示模型组大鼠E-cadherin在肾小管中的分布明显减少,α-SMA分布有所增多,肾小管出现了转分化。β-CM-7拮抗了这种变化,两种蛋白的蛋白表达结果与mRNA表达结果一致。结论：β-CM-7能够抑制糖尿病肾病大鼠肾脏的氧化应激和肾小管上皮-肌成纤维细胞的转分化。增强抗氧化能力,抑制TEMT可能是β-CM-7保护糖尿病肾病大鼠肾损伤的机制之一
3β-CM-7对糖尿病肾病大鼠肾局部肾素-血管紧张素系统的影响
上一章的结果提示β-CM-7保护糖尿病肾病大鼠肾损伤的作用可能与其增强肾脏抗氧化能力,抑制肾小管上皮-肌成纤维细胞的转分化有关。本章将从肾素-血管紧张素系统(Renin-angiotensin system, RAS)途径进一步探讨3-CM-7保护糖尿病肾病大鼠肾损伤的新的机制。试验大鼠及处理同第一章。取第一章各组大鼠肾脏进行如下试验：放射免疫法(RIA)测定大鼠肾脏组织中AngⅡ的含量；Real-time PCR检测大鼠肾脏组织中ACE、AT1、ACE2和MAS的mRNA表达；Western blot检测大鼠肾脏组织中ACE和ACE2蛋白的表达。结果：1)与对照组大鼠比较,模型组大鼠肾脏组织中AngⅡ的含量极显著升高(P<0.01)；灌胃β-CM-7后降低了肾脏局部AngⅡ (P=0.035)的含量,但仍高于对照组；2)与对照组比较,模型组大鼠肾脏组织中ACE2mRNA及蛋白的表达均显著降低(P<0.05),ACE mRNA和蛋白及AT1受体mRNA的表达显著升高(P<0.05), MAS mRNA表达略有降低,差异不显著(P=0.09)。β-酪啡肽-7显著上调了ACE2mRNA及蛋白的表达(P<0.05),ACE mRNA和蛋白及AT1受体的mRNA表达均降低(P<0.05), MAS mRNA的表达水平略有升高(P=0.07)；3)模型组大鼠肾脏中ACE/ACE2mRNA和ACE蛋白/ACE2蛋白的比值均显著高于对照组(P<0.01)；灌胃β-CM-7后,两比值均显著降低(P<0.05)。结论：糖尿病肾病时,肾脏局部RAS处于激活状态,ACE-AngⅡ-AT1轴活性占优势,高水平的AngⅡ参与了肾脏的损伤及纤维化。β-CM-7能够通过升高ACE2的表达,降低AngⅡ的高水平和AT1受体的表达,抑制RAS的过度激活,抑制糖尿病肾病大鼠的肾损伤。AngⅡ是糖尿病肾病大鼠肾损伤的关键因素,也可能是β-CM-7抑制糖尿病肾病大鼠肾损伤的关键通路。
4β-CM-7对AngⅡ刺激的肾小管上皮细胞氧化应激及转分化影响的细胞学研究
在细胞水平上深入探讨β-CM-7对AngⅡ诱导的细胞氧化应激及肾小管上皮-肌成纤维细胞转分化(TEMT)(?)(?)影响及其机制。方法采用DMEM培养基对NRK-52E肾小管上皮细胞进行体外培养,细胞分为对照组(Control group)、AngⅡ处理组(AngⅡ group)、β-酪啡肽-7干预组(β-CM-7group)及AT1受体阻断剂组(ARB group)。AngⅡ处理组于培养基中添加1nM的AngⅡ,β-CM-7干预组于培养基中加入1nM的AngⅡ及10-5M的β-CM-7, AT1受体阻断剂组于培养基中添加1nM的AngⅡ及10-5mol/L洛沙坦,对照组等量DMEM培养液；处理72h后,收集细胞及上清。生化法检测肾小管上皮细胞中氧化应激及抗氧化应激指标；Real-time PCR检测肾小管上皮细胞转分化、RAS主要因子及转化生长因子-β1(Transforming growth factor-β1, TGF-β1)等相关蛋白的mRNA表达；Western-blot及免疫荧光检测细胞转分化、RAS等相关蛋白的表达；RIA及ELISA分别检测细胞上清中AngⅡ及TGF-β1的含量。结果：1)AngⅡ处理NRK-52E肾小管上皮细胞,其中ROS及MDA的含量显著升高(P<0.01),SOD及GPx的活性显著降低(P<0.01),细胞发生氧化应激；β-CM-7干预可显著降低ROS及MDA的含量,升高SOD及GPx的活性；2) AngⅡ处理能够上调NRK-52细胞中α-SMA的mRNA及蛋白表达(P<0.01),下调E-cadherin mRNA及蛋白表达(P<0.01),AT1受体阻断剂可以拮抗这种作用。β-CM-7处理能够显著抑制AngⅡ引起α-SMA及E-cadherin的表达变化；3)AngⅡ处理的NRK-52E细胞中ACE2mRNA及蛋白的表达显著降低(P<0.05),ACE mRNA(P<0.01)及蛋白(P<0.05)的表达显著升高,TGF-β1的含量显著升高；β-CM-7干预显著上调了细胞中ACE2mRNA及蛋白的表达,下调ACE mRNA及蛋白的表达,AngⅡ及TGF-β1的含量均降低。结论：AngⅡ可以通过AT1受体,升高TGF-β1,介导NRK-52E细胞氧化应激及转分化; β-CM-7能够有效抑制AngⅡ介导的肾小管上皮细胞的氧化应激及转分化；其机制是：升高ACE2的表达,抑制ACE的表达,降低AngⅡ及TGF-β1的含量
In this study, effects of beta-casomorphin-7on renal funtion, morphological changes, oxidative stress, tubular epithelial-myofibroblast transdifferentiation (TEMT) and renin-angiotensin system (RAS) were first evaluated on the rats with diabetic nephropathy which were induced by STZ. The damage responses of AngⅡ on renal tubular epithelial cells were detected in vitro and studied the mechanism of beta-casomorphin-7on renal injury of rats. The research included four parts:
1The protective effect of β-casomorphin-7on renal injury on rats with diabetic nephropathy
This study was designed to investigate the protective effect of P-casomorphin-7on renal injury of streptozotocin-induced diabetic rats. Eight SD rats were selected as the control group in40rats,32rats were induced by intraperitoneal injection of STZ (60mg/kg body weight) to make the diabetic model. The diabetic rats were divided into model group which were given intragastric administration of saline and β-casomorphins-7group (β-CM-7group) which were given intragastric administration of7.5×10-6mol/kg body weight β-casomorphin-7. The food intake, water intake and the body weight were measured every day. The fasting blood glucose was measured every5days. All rats were sacrificed after30days of feeding with or without β-casomorphin-7, the serum and the kidney were collected and8rats were selected from every group for the following experiments:1) The urine glucose, urine protein, renal function, serum insulin and glucogan were detected.2) The pathological and fibrosis of kidney were detected by HE, MASSON and Sirius red.3) The mRNA and protein expression of type Ⅰ and IVcollagen in the kidney of rats were detected. Results:1)27rats were successfully induced into diabetic model in32rats and successful rate is84%. During the experiment, the water intake and food intake were increased significantly, the body weight was decreased significantly, the fasting blood glucose had been higher than16.7mmol/L during the experiment, the content of insulin was decreased (P<0.05) and the content of glucagon (P<0.05) was increased in the rats of model group. Compared with the rats of model group, β-CM-7decreased the food intake, water intake and fasting blood glucose, increased the body weight.2) After30days treatment, the urine glucose, urine protein, serum creatinine, blood urea nitrogen (P<0.05) and renal index (P<0.01) in the rats of model group were significantly increased and the kidney had obvious histopathological changes, β-casomorphin-7decreased the above index and renal histopathological changes.3) There were excessive deposition of collagen fibers in glomerulus and tubulointerstitial in the rats of model group, the mRNA and protein of type Ⅰ and Ⅳ collagen were significantly increased in the kidney of model group (P<0.05), β-casomorphin-7reduced deposition of collagen fibers in kidney of diabetic rats. Conclusions:Intraperitoneal injection of STZ could been used for inducing the diabetic nephropathy which first performed that more water intake, more food intake and loss of weight, and after30days the rats in model group performed glycosuria, proteinuria, renal hypertrophy, renal dysfuction and renal fibrosis. β-casomorphin-7had a protective effect on the kidney of rats with diabetic nephropathy induced by STZ.
2The possible mechanism of β-CM-7on renal injury of rats with diabetic nephropathy
We had found that β-CM-7had the protective effect on renal injury of rats with diabetic nephropathy in the previous experiment and this study explored the possible mechanism from the oxidative stress and renal tubular epithelial-myofibroblast transdifferentiation (TEMT). All rats were treated the same as the first chapter and the kidney were collected for the following experiments:1) The contents of MDA and H2O2, the SOD, GPx and T-AOC were determined by biochemical assay.2) Expression of α-smooth muscle actin (α-SMA), E-cadherin, vimentin and cytokeratinl9(CK19) mRNA in the rats were detected by real-time PCR. The protein expression and distribution of α-SMA and E-cadherin were detected by Western-blot and immunohistochemistry. Results:1) The activity of SOD and GPx (P<0.01) were significant lower and the contents of MDA (P<0.01) were significant higher than the control group in the kidney. β-CM-7increased the SOD (P<0.01), GPx (P<0.05), and decreased the MDA (P<0.05) of rats with diabetic nephropathy. The contents of T-AOC and H2O2in β-CM-7group were between control group and model group, but there is no statistics significance (P>0.05).2) Compared with the control group, the mRNA expression of α-SMA (P<0.01) and vimentin (P<0.05) increased significantly and the expression of E-cadherin (P<0.05) and CK19(P<0.01) mRNA were reduced in model group. β-CM-7reduced the mRNA expression of α-SMA and vimentin (P<0.05), increase the mRNA expression of E-cadherin (P<0.05) and CK19(P<0.01).3) The distribution of E-cadherin was decreased significantly and the α-SMA was increased significantly, renal tubular epithelial cell appeared tubular epithelial-myofibroblast transdifferentiation and β-casomorphin-7antagonized all these changes. The protein expression of E-cadherin and α-SMA were consistent with the expression of mRNA. Conclusion:β-CM-7reduced renal oxidative stress and renal tubular epithelial-myofibroblast transdifferentiation which may be one of the protective mechanisms of β-CM-7on renal injury
3The effect of β-casomorphin-7on RAS of kidney in the rats with diabetic nephropathy
We had found that β-CM-7had the protective effect on renal injury of rats with diabetic nephropathy which was associated with enhancing the antioxidant capacity and inhibiting the renal tubular epithelial-myofibroblast transdifferentiation (TEMT) in the previous experiment. To further explore the new mechanism of beta-casomorphin-7on the renal injury of rats with diabetic nephropathy from the renin-angiotensin system (RAS) in this experiment. All rats were treated the same as the first chapter and the kidney were collected for the following experiments:The content of AngⅡin the kidney of rats were detected by radioimmunoassay. Expression of ACE, AT1, ACE2and MAS mRNA in the kidney of rats were detected by real-time PCR. The protein expression of ACE and ACE2were detected by Western-blqt. Results:1) Compared with control group, content of AngⅡ (P<0.01) was significantly increased in the kidney of rats in model group (P<0.01). β-casomorphin-7decreased content of AngⅡ (P=0.035), but it was also higher than the control group.2) Compared with control group, the expression of ACE2mRNA and protein (P<0.05) was decreased significantly, the expression of ACE protein and mRNA, the AT1mRNA were significantly increased (P<0.05), the expression of MAS mRNA was decreased (P=0.09) which did not have statistical significance in the kidney of model group. β-CM-7could increased the expression of ACE2mRNA and protein(P<0.05), decrease the expression of ACE mRNA and protein, AT1mRNA (P<0.05) and MAS mRNA (P=0.07) in the kidney significantly. The ratio of ACE/ACE2mRNA and ACE/ACE2protein was higher in the kidney of the model group than the control group (P<0.01), β-CM-7decreased the ratio of ACE/ACE2(P<0.05). Conclusion:The RAS were activated in the kidney of rats with diabetic nephropathy and the axis of ACE-AngⅡ-AT1was dominant. The high contents of Angll involved in the renal injury and fibrosis. β-casomorphin-7protected the renal injury and fibrosis of rats with diabetic nephropathy through increasing the expression of ACE2, decreasing the content of AngⅡ and the expression of AT1. AngⅡ was a key factor in renal injury of rats with diabetic nephropathy and it may be a key pathway which β-CM-7protected the renal injury of rats with diabetic nephropathy.
4The effect of β-casomorphin-7on the oxidative stress and TEMT of cells treated with AngⅡ in vitro
The research is further to study the effect and mechanism of β-casomorphin-7on the oxidative stress and tubular epithelial-myofibroblast transdifferentiation (TEMT) of NRK-52E cells treated with AngⅡ. NRK-52E cells were cultured in the DMEM medium and the cells were divided into four group:control group, AngⅡ group, β-CM-7group and AT1receptor blocker group (ARB group). The cells of the AngⅡ group were treated with lnM AngⅡ in DMEM medium, the cells of β-CM-7group were treated with lnM AngⅡ and10-5M β-casomorphin-7in DMEM medium, the cells of ARB group were treated with lnM AngⅡ and10-5M losartan in DMEM medium and the cells of control group were cultured in DMEM medium. All cells were treated for72h and the cells and the culture medium were collected. The index of oxidative stress and antioxidant were detected by biochemical assay. The mRNA expression about TEMT, RAS and TGF-β1were detected by real-time PCR. The protein expression about TEMT and RAS were detected by western-blot and immunofluorescence. The contents of Angll or TGF-β1were detected by radioimmunoassay or ELISA. Result:1) The contents of ROS and MDA were increased (P<0.01) and the SOD and GPx were decreased (P<0.01) in the cells treated with Angll, which increased the oxidative stress of cells. P-CM-7significantly reduced the contents of ROS and MDA, increase the activity of SOD and GPx in the NRK-52E cells treated with Angll, which alleviated the oxidative stress of cells.2) The mRNA and protein expression of α-SMA (P<0.01) was increased and E-cadherin (P<0.01) was decreased in the NRK-52E cells treated with Angll, AT1receptor blocker (ARB) antagonized this changes of α-SMA and E-cadherin and β-CM-7also significantly alleviated the changes of α-SMA and E-cadherin of cells.3) The mRNA and protein expression of ACE was increased (P<0.05), ACE2was decreased (P<0.01&P<0.05)) and the content of TGF-β1was increased in the cells treated with AngⅡ. β-CM-7significantly increase the mRNA and protein expression of ACE2, decrease the mRNA and protein expression of ACE and the contents of AngⅡ and TGF-β1. Conclusion:The oxidative stress and TEMT of NRK-52E cells could be induced by AngⅡ through AT1receptor and TGF-β1. β-CM-7alleviated the oxidative stress and TEMT of NRK-52E cell treated with AngⅡ which is associated with increasing the expression of ACE2, decreasing the expression of ACE and the contents of Ang Ⅱ and TGF-β1.
引文
[1]Selman K, Kafatos FC. Transdifferentiation in the labial gland of silk moths:Is DNA required for cellular metamorphosis?[J]. Cell Differ.1974,3:81-94
[2]Carew RM, Wang B, Kantharidis P. The role of emt in renal fibrosis[J]. Cell Tissue Res. 2012,347:103-116
[3]Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition[J]. J. Clin. Invest. 2009,119:1420-1428
[4]Liu YH. Epithelial to mesenchymal transition in renal fibrogenesis:Pathologic significance, molecular mechanism, and therapeutic intervention[J]. J. Am. Soc. Nephrol.2004,15:1-12
[5]Strutz F, Okada H, Lo CW, et al. Identification and characterization of a fibroblast marker:Fsp1[J]. J. Cell Biol.1995,130:393-406
[6]付平,何成奇,柳飞,等.肾纤复元胶囊延缓5/6肾切除大鼠肾衰进展机制的实验研究[J].四川大学学报：医学版.2006,37：430-433
[7]Lian Y-g, Zhou Q-g, Zhang Y-j, et al. Vegf ameliorates tubulointerstitial fibrosis in unilateral ureteral obstruction mice via inhibition of epithelial-mesenchymal transition[J]. Acta Pharmaco Sin. 2011,32:1513-1521
[8]Qi W, Chen X, Holian J, et al. Transforming growth factor-beta(1) differentially mediates fibronectin and inflammatory cytokine expression in kidney tubular cells[J]. Am. J. Physiol-Renal. 2006,291:F1070-F1077
[9]Kalluri R, Neilson EG. Epithelial-mesenchymal transition and its implications for fibrosis[J]. J. Clin. Invest.2003,112:1776-1784
[10]Iwano M, Plieth D, Danoff TM, et al. Evidence that fibroblasts derive from epithelium during tissue fibrosis[J]. J. Clin. Invest.2002,110:341-350
[11]Gomez-Alamillo C, Benito-Hernandez A, Ramos-Barron MA, et al. Analysis of urinary gene expression of epithelial-mesenchymal transition markers in kidney transplant recipients[J]. Transplant. Proc.2010,42:2886-2888
[12]Bhowmick NA, Ghiassi M, Bakin A, et al. Transforming growth factor-beta 1 mediates epithelial to mesenchymal transdifferentiation through a rhoa-dependent mechanism[J]. Mol. Biol. Cell. 2001,12:27-36
[13]Boutet A, De Frutos CA, Maxwell PH, et al. Snail activation disrupts tissue homeostasis and induces fibrosis in the adult kidney[J]. EMBO J.2006,25:5603-5613
[14]Brownlee M. Biochemistry and molecular cell biology of diabetic complications[J]. Nature. 2001,414:813-820
[15]Strutz F, Zeisberg M, Ziyadeh FN, et al. Role of basic fibroblast growth factor-2 in epithelial-mesenchymal transformation[J]. Kidney Int.2002,61:1714-1728
[16]Rastaldi MP, Ferrario F, Giardino L, et al. Epithelial-mesenchymal transition of tubular epithelial cells in human renal biopsies[J]. Kidney Int.2002,62:137-146
[17]Bienz M. Beta-catenin:A pivot between cell adhesion and wnt signalling[J]. Curr. Biol. 2005,15:R64-R67
[18]Kaimori A, Potter J, Kaimori J-y, et al. Transforming growth factor-beta 1 induces an epithelial-to-mesenchymal transition state in mouse hepatocytes in vitro[J]. J. Biol. Chem.2007,282: 22089-22101
[19]Burney BO, Kalaitzidis RG, Bakris GL. Novel therapies of diabetic nephropathy[J]. Curr. Opin. Nephrol. Hypertens.2009,18:107-111
[20]Burns WC, Twigg SM, Forbes JM, et al. Connective tissue growth factor plays an important role in advance glycation end product-induced tubular epithelial-to-mesenchymal transition:Implications for diabetic renal disease[J]. J. Am. Soc. Nephrol.2006,17:2484-2494
[21]Yang JW, Liu YH. Dissection of key events in tubular epithelial to myofibroblast transition and its implications in renal interstitial fibrosis[J]. Am. J. Pathol.2001,159:1465-1475
[22]Nath KA. The tubulointerstitium in progressive renal disease[J]. Kidney Int.1998,54:992-994
[23]Lee JM, Dedhar S, Kalluri R, et al. The epithelial-mesenchymal transition:New insights in signaling, development, and disease[J]. J. Cell Biol.2006,172:973-981
[24]Yu L, Border WA, Huang YF, et al. Tgf-beta isoforms in renal fibrogenesis[J]. Kidney Int. 2003,64:844-856
[25]Fan J-M, Ng Y-Y, Hill PA, et al. Transforming growth factor-&bgr; regulates tubular epithelial-myofibroblast transdifferentiation in vitro[J]. Kidney Int.1999,56:1455-1467
[26]Li JH, Zhu H-J, Huang XR, et al. Smad7 inhibits fibrotic effect of tgf-β on renal tubular epithelial cells by blocking smad2 activation[J]. J. Am. Soc. Nephrol.2002,13:1464-1472
[27]Phanish M, Wahab N, Colville-Nash P, et al. The differential role of smad2 and smad3 in the regulation of pro-fibrotic tgfbetal responses in human proximal-tubule epithelial cells[J]. Biochem. J.2006,393:601-607
[28]Bakin AV, Tomlinson AK, Bhowmick NA, et al. Phosphatidylinositol 3-kinase function is required for transforming growth factor beta-mediated epithelial to mesenchymal transition and cell migration[J]. J. Biol. Chem.2000,275:36803-36810
[29]Cano A, Perez-Moreno MA, Rodrigo I, et al. The transcription factor snail controls epithelial-mesenchymal transitions by repressing e-cadherin expression[J]. Nat Cell Biol.2000,2: 76-83
[30]Li Y, Yang J, Dai C, et al. Role for integrin-linked kinase in mediating tubular epithelial to mesenchymal transition and renal interstitial fibrogenesis[J]. J. Clin. Invest.2003,112:503-516
[31]Kim K, Lu ZF, Hay ED. Direct evidence for a. Role of beta-catenin/lef-1 signaling pathway in induction of emt[J]. Cell Biol. Int.2002,26:463-476
[32]Burns WC, Twigg SM, Forbes JM, et al. Connective tissue growth factor plays an important role in advanced glycation end product-induced tubular epithelial-to-mesenchymal transition:Implications for diabetic renal disease[J]. J. Am. Soc. Nephrol.2006,17:2484-2494
[33]Gupta S, Clarkson MR, Duggan J, et al. Connective tissue growth factor:Potential role in glomerulosclerosis and tubulointerstitial fibrosis[J]. Kidney Int.2000,58:1389-1399
[34]Qi W, Twigg S, Chen X, et al. Integrated actions of transforming growth factor-beta(1) and connective tissue growth factor in renal fibrosis[J]. Am. J. Physiol-Renal.2005,288:F800-F809
[35]Qi W, Chen X, Poronnik P, et al. Transforming growth factor-beta/connective tissue growth factor axis in the kidney[J]. Int. J. Biochem. Cell Biol.2008,40:9-13
[36]Wahab NA, Yevdokimova N, Weston BS, et al. Role of connective tissue growth factor in the pathogenesis of diabetic nephropathy[J]. Biochem. J.2001,359:77-87
[37]Paul M, Mehr AP, Kreutz R. Physiology of local renin-angiotensin systems[J]. Physiol. Rev.2006, 86:747-803
[38]Yang JW, Dai CS, Liu YH. Hepatocyte growth factor gene therapy and angiotensin ii blockade synergistically attenuate renal interstitial fibrosis in mice[J]. J. Am. Soc. Nephrol.2002,13: 2464-2477
[39]Rhyu DY, Yang Y, Ha H, et al. Role of reactive oxygen species in tgf-β1-induced mitogen-activated protein kinase activation and epithelial-mesenchymal transition in renal tubular epithelial cells[J]. J. Am. Soc. Nephrol.2005,16:667-675
[40]Nishikawa T, Edelstein D, Brownlee M. The missing link:A single unifying mechanism for diabetic complications[J]. Kidney Int. Suppl.2000,77:S26-30
[41]Fan JM, Huang XR, Ng YY, et al. Interleukin-1 induces tubular epithelial-myofibroblast transdifferentiation through a transforming growth factor-beta 1-dependent mechanism in vitro[J]. Am. J. Kidney Dis.2001,37:820-831
[42]Cheng SF, Lovett DH. Gelatinase a (mmp-2) is necessary and sufficient for renal tubular cell epithelial-mesenchymal transformation[J]. Am. J. Pathol.2003,162:1937-1949
[43]Zeisberg M, Hanai J, Sugimoto H, et al. Bmp-7 counteracts tgf-beta 1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury[J]. Nat. Med.2003,9: 964-968
[44]Yang JW, Liu YH. Blockage of tubular epithelial to myofibroblast transition by hepatocyte growth factor prevents renal interstitial fibrosis[J]. J. Am. Soc. Nephrol.2002,13:96-107
[45]de Laplanche E, Gouget K, Cleris G, et al. Physiological oxygenation status is required for fully differentiated phenotype in kidney cortex proximal tubules[J]. Am. J. Physiol-Renal.2006,291: F750-F760
[46]Okada H, Danoff TM, Kalluri R, et al. Early role of fspl in epithelial-mesenchymal transformation[J]. Am. J. Physiol-Renal.1997,273:F563-F574
[47]Schena FP, Gesualdo L. Pathogenetic mechanisms of diabetic nephropathy[J]. J. Am. Soc. Nephrol. 2005,16:S30-S33
[48]Gilbert RE, Cooper ME. The tubulointerstitium in progressive diabetic kidney disease:More than an aftermath of glomerular injury?[J]. Kidney Int.1999,56:1627-1637
[49]Nath KA. Tubulointerstitial changes as a major determinant in the progression of renal damage[J]. Am. J. Kidney Dis.1992,20:1-17
[50]Badid C, Desmouliere A, Babici D, et al. Interstitial expression of alpha-sma:An early marker of chronic renal allograft dysfunction[J]. Nephrol Dial Transpl.2002,17:1993-1998
[51]Peinado H, Quintanilla M, Cano A. Transforming growth factor beta-1 induces snail transcription factor in epithelial cell lines-mechanisms for epithelial mesenchymal transitions [J]. J. Biol. Chem. 2003,278:21113-21123
[52]Burns WC, Kantharidis P, Thomas MC. The role of tubular epithelial-mesenchymal transition in progressive kidney disease[J]. Cells Tissues Organs.2007,185:222-231
[53]Yamaguchi Y, Iwano M, Suzuki D, et al. Epithelial-mesenchymal transition as a potential explanation for podocyte depletion in diabetic nephropathy[J]. Am. J. Kidney Dis.2009,54:653-664
[54]Mauer M, Zinman B, Gardiner R, et al. Renal and retinal effects of enalapril and losartan in type 1 diabetes[J]. N. Engl. J. Med.2009,361:40-51
[55]Halawa B. Combination therapy in primary hypertension[J]. Polski merkuriusz lekarski:organ Polskiego Towarzystwa Lekarskiego.1998,4:35-38
[56]Hill C, Flyvbjerg A, Rasch R, et al. Transforming growth factor-beta 2 antibody attenuates fibrosis in the experimental diabetic rat kidney[J]. J. Endocrinol.2001,170:647-651
[57]Yokoi H, Mukoyama M, Nagae T, et al. Reduction in connective tissue growth factor by antisense treatment ameliorates renal tubulointerstitial fibrosis[J]. J. Am. Soc. Nephrol.2004,15:1430-1440
[58]Zeisberg M, Duffield JS. Resolved:Emt produces fibroblasts in the kidney[J]. J. Am. Soc. Nephrol. 2010,21:1247-1253
[59]Yang J, Dai C, Liu Y. Systemic administration of naked plasmid encoding hepatocyte growth factor ameliorates chronic renal fibrosis in mice[J]. Gene Ther.2001,8:1470-1479
[60]Hills CE, Brunskill NJ. Cellular and physiological effects of c-peptide[J]. Clin. Sci. 2009,116:565-574
[61]Kellner D, Chen J, Richardson I, et al. Angiotensin receptor blockade decreases fibrosis and fibroblast expression in a rat model of unilateral ureteral obstruction[J]. J Urology.2006,176: 806-812
[62]Duan S-B, Liu G-L, Wang Y-H, et al. Epithelial-to-mesenchymal transdifferentiation of renal tubular epithelial cell mediated by oxidative stress and intervention effect of probucol in diabetic nephropathy rats[J]. Ren. Fail.2012,34:1244-1251
[63]He W, Kang YS, Dai C, et al. Blockade of wnt/beta-catenin signaling by paricalcitol ameliorates proteinuria and kidney injury[J]. J. Am. Soc. Nephrol.2011,22:90-103
[64]Reese S, Vidyasagar A, Jacobson L, et al. The pin 1 inhibitor juglone attenuates kidney fibrogenesis via pin 1-independent mechanisms in the unilateral ureteral occlusion model[J]. Fibrogenesis & tissue repair.2010,3:1-1
[65]Aresu L, Benali S, Garbisa S, et al. Matrix metalloproteinases and their role in the renal epithelial mesenchymal transition[J]. Histol. Histopathol.2011,26:307-313
[66]Packham DK, Alves TP, Dwyer JP, et al. Relative incidence of esrd versus cardiovascular mortality in proteinuric type 2 diabetes and nephropathy:Results from the diametric (diabetes mellitus treatment for renal insufficiency consortium) database[J]. Am. J. Kidney Dis.2012,59:75-83
[67]Parving H-H. Diabetic nephropathy:Prevention and treatment[J]. Kidney Int.2001,60:2041-2055
[68]Brownlee M. The pathobiology of diabetic complications a unifying mechanism[J]. Diabetes.2005, 54:1615-1625
[69]Hakim FA, Pflueger A. Role of oxidative stress in diabetic kidney disease[J]. Medical science monitor:international medical journal of experimental and clinical research.2010,16:RA37
[70]Ruster C, Wolf G. Renin-angiotensin-aldosterone system and progression of renal disease[J]. J. Am. Soc. Nephrol.2006,17:2985-2991
[71]Kim S-M, Kim Y-G, Jeong K-H, et al. Angiotensin ii-induced mitochondrial nox4 is a major endogenous source of oxidative stress in kidney tubular cells[J]. Plos One.2012,7:e39739-e39739
[72]Whiting DR, Guariguata L, Weil C, et al. Idf diabetes atlas:Global estimates of the prevalence of diabetes for 2011 and 2030[J]. Diabetes Res. Clin. Pract.2011,94:311-321
[73]Fioretto P, Mauer M. Histopathology of diabetic nephropathy[C]. Seminars in nephrology. 2007;27:195-207
[74]Remuzzi G, Schieppati A, Ruggenenti P. Nephropathy in patients with type 2 diabetes[J]. N. Engl. J. Med.2002,346:1145-1151
[75]Galle J. Oxidative stress in chronic renal failure[J]. Nephrol Dial Transpl.2001,16:2135-2137
[76]Nishikawa T, Edelstein D, Du XL, et al. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage[J]. Nature.2000,404:787-790
[77]Asaba K, Tojo A, Onozato ML, et al. Effects of nadph oxidase inhibitor in diabetic nephropathy[J]. Kidney Int.2005,67:1890-1898
[78]Kang S-W, Natarajan R, Shahed A, et al. Role of 12-lipoxygenase in the stimulation of p38 mitogen-activated protein kinase and collagen a5 (iv) in experimental diabetic nephropathy and in glucose-stimulated podocytes[J]. J. Am. Soc. Nephrol.2003,14:3178-3187
[79]Kanwar YS, Wada J, Sun L, et al. Diabetic nephropathy:Mechanisms of renal disease progression[J]. Exp. Biol. Med.2008,233:4-11
[80]Lehmann R, Schleicher ED. Molecular mechanism of diabetic nephropathy [J]. Clin. Chim. Acta. 2000,297:135-144
[81]Yard B, Kahlert S, Engelleiter R, et al. Decreased glomerular expression of agrin in diabetic nephropathy and podocytes, cultured in high glucose medium[J]. Exp. Nephrol.2001,9:214-222
[82]Susztak K, Raff AC, Schiffer M, et al. Glucose-induced reactive oxygen species cause apoptosis of podocytes and podocyte depletion at the onset of diabetic nephropathy [J]. Diabetes.2006,55: 225-233
[83]Fukami K, Ueda S, Yamagishi S-i, et al. Ages activate mesangial tgf-β-smad signaling via an angiotensin ii type i receptor interaction[J]. Kidney Int.2004,66:2137-2147
[84]Liu Y. Epithelial to mesenchymal transition in renal fibrogenesis:Pathologic significance, molecular mechanism, and therapeutic intervention[J]. J. Am. Soc. Nephrol.2004,15:1-12
[85]Ha H, Yu MR, Choi YJ, et al. Role of high glucose-induced nuclear factor-κb activation in monocyte chemoattractant protein-1 expression by mesangial cells[J]. J. Am. Soc. Nephrol.2002,13: 894-902
[86]HA H, LEE HB. Reactive oxygen species amplify glucose signalling in renal cells cultured under high glucose and in diabetic kidney[J]. Nephrology.2005,10:S7-S10
[87]Seghieri G, Di Simplicio P, Anichini R, et al. Platelet antioxidant enzymes in insulin-dependent diabetes mellitus[J]. Clin. Chim. Acta.2001,309:19-23
[88]Fujita H, Fujishima H, Chida S, et al. Reduction of renal superoxide dismutase in progressive diabetic nephropathy [J]. J. Am. Soc. Nephrol.2009,20:1303-1313
[89]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. 2001,50:2114-2125
[90]Saklayen MG, Yap J, Vallyathan V. Effect of month-long treatment with oral n-acetylcysteine on the oxidative stress and proteinuria in patients with diabetic nephropathy:A pilot study[J]. J. Investig. Med.2010,58:28-31
[91]Turner AJ, Hooper NM. The angiotensin-converting enzyme gene family:Genomics and pharmacology[J]. Trends Pharmacol. Sci.2002,23:177-183
[92]Rosivall L. Intrarenal renin-angiotensin system[J]. Mol. Cell. Endocrinol.2009,302:185-192
[93]Zaman MA, Oparil S, Calhoun DA. Drugs targeting the renin-angiotensin-aldosterone system[J]. Nat Rev Drug Discov.2002,1:621-636
[94]Corvol P, Michaud A, Soubrier F, et al. Recent advances in knowledge of the structure and function of the angiotensin-i converting-enzyme[J]. J. Hypertens.1995,13:S3-S10
[95]Donoghue M, Hsieh F, Baronas E, et al. A novel angiotensin-converting enzyme-related carboxypeptidase (ace2) converts angiotensin i to angiotensin 1-9[J]. Circ. Res.2000,87:E1-E9
[96]Rice GI, Thomas DA, Grant PJ, et al. Evaluation of angiotensin-converting enzyme (ace), its homologue ace2 and neprilysin in angiotensin peptide metabolism[J]. Biochem. J.2004,383:45-51
[97]Tipnis SR, Hooper NM, Hyde R, et al. A human homolog of angiotensin-converting enzyme-cloning and functional expression as a captopril-insensitive carboxypeptidase[J]. J. Biol. Chem. 2000,275:33238-33243
[98]Santos RAS, Ferreira AJ, Pinheiro SVB, et al. Angiotensin-(1-7) and its receptor as a potential targets for new cardiovascular drugs[J]. Expert Opin InvDrug.2005,14:1019-1031
[99]Chappel MC, Ferrario CM. Ace and ace2:Their role to balance the expression of angiotensin ii and angiotensin-(1-7)[J]. Kidney Int.2006,70:8-10
[100]Bader M, Ganten D. Update on tissue renin-angiotensin systems[J]. J Mol Medi.2008,86:615-621
[101]Ganten D, Minnich JL, Grenger P, et al. Angiotensin-forming enzyme in brain tissue[J]. Science. 1971,173:64-65
[102]Lavoie JL, Sigmund CD. Minireview:Overview of the renin-angiotensin system-an endocrine and paracrine system[J]. Endocrinology.2003,144:2179-2183
[103]Carey RM, Siragy HM. Newly recognized components of the renin-angiotensin system:Potential roles in cardiovascular and renal regulation[J]. Endocr. Rev.2003,24:261-271
[104]Berry C, Touyz R, Dominiczak A, et al. Angiotensin receptors:Signaling, vascular pathophysiology, and interactions with ceramide[J]. Am J Physiol-C.2001,281:H2337-H2365
[105]Miyata N, Park F, Li XF, et al. Distribution of angiotensin atl and at2 receptor subtypes in the rat kidney[J]. Am. J. Physiol-Renal.1999,277:F437-F446
[106]Gembardt F, Sterner-Kock A, Imboden H, et al. Organ-specific distribution of ace2 mrna and correlating peptidase activity in rodents[J]. Peptides.2005,26:1270-1277
[107]Bader M. Ace2, angiotensin-(1-7), and mas:The other side of the coin[J]. Pflug Arch Eur J Phy. 2013,465:79-85
[108]Zimpelmann J, Kumar D, Levine DZ, et al. Early diabetes mellitus stimulates proximal tubule renin mrna expression in the rat[J]. Kidney Int.2000,58:2320-2330
[109]Hostetter TH, Troy J, Brenner B. Glomerular hemodynamics in experimental diabetes mellitus[J]. Kidney Int.1981,19:410-415
[110]Rossig L, Hermann C, Haendeler J, et al. Angiotensin ii-induced upregulation of map kinase phosphatase-3 mrna levels mediates endothelial cell apotosis[J]. Basic Res. Cardiol.2002,97:1-8
[111]Kobori H, Nangaku M, Navar LG, et al. The intrarenal renin-angiotensin system:From physiology to the pathobiology of hypertension and kidney disease[J]. Pharmacol. Rev.2007,59:251-287
[112]Mezzano SA, Ruiz-Ortega M, Egido J. Angiotensin ii and renal fibrosis[J]. Hypertension. 2001,38:635-638
[113]Kagami S, Border WA, Miller DE, et al. Angiotensin ii stimulates extracellular matrix protein synthesis through induction of transforming growth factor-beta expression in rat glomerular mesangial cells[J]. J. Clin. Invest.1994,93:2431
[114]Barnett AH, Bain SC, Bouter P, et al. Angiotensin-receptor blockade versus converting-enzyme inhibition in type 2 diabetes and nephropathy[J]. N. Engl. J. Med.2004,351:1952-1961
[115]Ye MH, Wysocki J, Naaz P, et al. Differential expression of angiotensin converting enzyme (ace) and ace-related carboxypeptidase (ace2) in diabetic db/db mice[J]. Hypertension.2004,43: 1352-1352
[116]Wysocki J, Ye MH, Soler MJ, et al. Ace and ace2 activity in diabetic mice[J]. Diabetes. 2006,55:2132-2139
[117]Tikellis C, Johnston CI, Forbes JM, et al. Characterization of renal angiotensin-converting enzyme 2 in diabetic nephropathy[J]. Hypertension.2003,41:392-397
[118]Mizuiri S, Hemmi H, Arita M, et al. Expression of ace and ace2 in individuals with diabetic kidney disease and healthy controls[J]. Am. J. Kidney Dis.2008,51:613-623
[119]Ye M, Wysocki J, William J, et al. Glomerular localization and expression of angiotensin-converting enzyme 2 and angiotensin-converting enzyme:Implications for albuminuria in diabetes[J]. J. Am. Soc. Nephrol.2006,17:3067-3075
[120]Liu CX, Hu Q, Wang Y, et al. Angiotensin-converting enzyme (ace) 2 overexpression ameliorates glomerular injury in a rat model of diabetic nephropathy:A comparison with ace inhibition[J]. Mol. Med.2011,17:59-69
[121]Soler MJ, Wysocki J, Ye M, et al. Ace2 inhibition worsens glomerular injury in association with increased ace expression in streptozotocin-induced diabetic mice[J]. Kidney Int.2007,72:614-623
[122]Shiota A, Yamamoto K, Ohishi M, et al. Loss of ace2 accelerates time-dependent glomerular and tubulointerstitial damage in streptozotocin-induced diabetic mice[J]. Hypertens. Res.2010,33: 298-307
[123]Nadarajah R, Milagres R, Dilauro M, et al. Podocyte-specific overexpression of human angiotensin-converting enzyme 2 attenuates diabetic nephropathy in mice[J]. Kidney Int.2012,82: 292-303
[124]Singh T, Singh K, Sharma PL. Ameliorative potential of angiotensin(1-7)/mas receptor axis in streptozotocin-induced diabetic nephropathy in rats[J]. Methods Find. Exp. Clin. Pharmacol.2010, 32:19-25
[125]Botelho-Santos GA, Bader M, Alenina N, et al. Altered regional blood flow distribution in mas-deficient mice[J]. Therapeutic advances in cardiovascular disease.2012,6:201-211
[126]Shao Y, He M, Zhou L, et al. Chronic angiotensin (1-7) injection accelerates stz-induced diabetic renal injuryl[J]. Acta Pharmacol Sin.2008,29:829-837
[127]Jandeleit-Dahm K, Cooper ME. Hypertension and diabetes:Role of the renin-angiotensin system[J]. Endocrinol. Metab. Clin. North Am.2006,35:469-490
[128]Paravicini TM, Touyz RM. Redox signaling in hypertension[J]. Cardiovasc. Res.2006,71:247-258
[129]Shah SV, Baliga R, Rajapurkar M, et al. Oxidants in chronic kidney disease[J]. J. Am. Soc. Nephrol.2007,18:16-28
[130]Wilson S. Role of oxygen-derived free radicals in acute angiotensin ii--induced hypertensive vascular disease in the rat[J]. Circ. Res.1990,66:722-734
[131]Wang D, Chen Y, Chabrashvili T, et al. Role of oxidative stress in endothelial dysfunction and enhanced responses to angiotensin ii of afferent arterioles from rabbits infused with angiotensin ii[J]. J. Am. Soc. Nephrol.2003,14:2783-2789
[132]Zafari AM, Ushio-Fukai M, Akers M, et al. Role of nadh/nadph oxidase-derived h2o2 in angiotensin ii-induced vascular hypertrophy [J]. Hypertension.1998,32:488-495
[133]Loot AE, Schreiber JG, Fisslthaler B, et al. Angiotensin ii impairs endothelial function via tyrosine phosphorylation of the endothelial nitric oxide synthase[J]. J Exp Med.2009,206:2889-2896
[134]Pueyo ME, Gonzalez W, Nicoletti A, et al. Angiotensin ii stimulates endothelial vascular cell adhesion molecule-1 via nuclear factor-κb activation induced by intracellular oxidative stress[J]. Arterioscler. Thromb. Vasc. Biol.2000,20:645-651
[135]An SJ, Boyd R, Zhu M, et al. Nadph oxidase mediates angiotensin ii-induced endothelin-1 expression in vascular adventitial fibroblasts[J]. Cardiovasc. Res.2007,75:702-709
[136]Kawahara T, Ritsick D, Cheng G, et al. Point mutations in the proline-rich region of p22phox are dominant inhibitors of noxl-and nox2-dependent reactive oxygen generation[J]. J. Biol. Chem. 2005,280:31859-31869
[137]Oudit GY, Herzenberg AM, Kassiri Z, et al. Loss of angiotensin-converting enzyme-2 leads to the late development of angiotensin ii-dependent glomerulosclerosis[J]. Am J Pathol.2006,168: 1808-1820
[138]Gwathmey TM, Pendergrass KD, Reid SD, et al. Angiotensin-(1-7)-angiotensin-converting enzyme 2 attenuates reactive oxygen species formation to angiotensin ii within the cell nucleus[J]. Hypertension.2010,55:166-171
[139]Zhong J, Guo D, Chen CB, et al. Prevention of angiotensin ⅱ-mediated renal oxidative stress, inflammation, and fibrosis by angiotensin-converting enzyme 2[J]. Hypertension.2011,57:314-322
[140]Giani JF, Burghi V, Veiras LC, et al. Angiotensin-(1-7) attenuates diabetic nephropathy in zucker diabetic fatty rats[J]. Am. J. Physiol-Renal.2012,302:F1606-F1615
[141]Benter IF, Yousif MH, Dhaunsi GS, et al. Angiotensin-(1-7) prevents activation of nadph oxidase and renal vascular dysfunction in diabetic hypertensive rats[J]. Am. J. Nephrol.2007,28:25-33
[142]Moon J-Y, Tanimoto M, Gohda T, et al. Attenuating effect of angiotensin-(1-7) on angiotensin ⅱ-mediated nad (p) h oxidase activation in type 2 diabetic nephropathy of kk-ay/ta mice[J]. Am. J. Physiol-Renal.2011,300:F1271-F1282
[143]Gonzales S, Noriega GO, Tomaro MaL, et al. Angiotensin-(1-7) stimulates oxidative stress in rat kidney[J]. Regul. Pept.2002,106:67-70
[144]Shao Y, He M, Zhou L, et al. Chronic angiotensin (1-7) injection accelerates stz-induced diabetic renal injury[J]. Acta Pharmacol Sin.2008,29:829-837
[145]Eigel W, Butler J, Ernstrom C, et al. Nomenclature of proteins of cow's milk:Fifth revision[J]. J. Dairy Sci.1984,67:1599-1631
[146]Ostersen S, Foldager J, Hermansen JE. Effects of stage of lactation, milk protein genotype and body condition at calving on protein composition and renneting properties of bovine milk[J]. J. Dairy Res.1997,64:207-219
[147]Brantl V, Teschemacher H, Henschen A, et al. Novel opioid peptides derived from casein (beta-casomorphins). I. Isolation from bovine casein peptone[J]. Hoppe. Seylers Z. Physiol. Chem. 1979,360:1211-1216
[148]Bradshaw J, White D. Identification of a major n-glycosylated protein of rabbit mammary gland and its appearance during development in vivo[J]. Int J Biochem.1985,17:175-185
[149]Mann D, Fraser H. The neonatal period:A critical interval in male primate development[J]. J. Endocrinol.1996,149:191-197
[150]宗亚峰.β酪啡肽在大鼠胃肠道内的释放、吸收和稳定特性及其对胃肠机能的影响[D].南京农业大学博士学位论文,2007.
[151]Schlimme E, Meisel H. Bioactive peptides derived from milk proteins. Structural, physiological and analytical aspects[J]. Food/Nahrung.1995,39:1-20
[152]Meisel H. Chemical characterization and opioid activity of an exorphin isolated from invivo digests of casein[J]. FEBS Lett.1986,196:223-227
[153]Kreil G, Umbach M, Brantl V, et al. Studies of the enzymatic degradation of β-casomorphins[J]. Life Sci.1983,33:137-140
[154]Kaminski S, Cieslinska A, Kostyra E. Polymorphism of bovine beta-casein and its potential effect on human health[J]. J Appl Genet.2007,48:189-198
[155]Froetschel M. Bioactive peptides in digesta that regulate gastrointestinal function and intake[J]. J. Anim. Sci.1996,74:2500-2508
[156]Hautefeuille M, Brantl V, Dumontier AM, et al. Beta-casomorphin derivatives decrease short-circuit current in rabbit ileum[J]. Gastroenterology.1985,88:1414-1414
[157]Schusdziarra V, Schick A, de la Fuente A, et al. Effect of beta-casomorphins and analogs on insulin release in dogs[J]. Endocrinology.1983,112:885-889
[158]Kil SJ, Froetschel MA. Involvement of opioid-peptides from casein on reticular motility and digesta passage in steers[J]. J. Dairy Sci.1994,77:111-123
[159]Morley JE, Levine A, Yamada T, et al. Effect of exorphins on gastrointestinal function, hormonal release, and appetite[J]. Gastroenterology.1983,84:1517-1523
[160]谈寅飞,邹思湘,陈伟华.β-酪啡肽-7对仔猪胃泌素分泌,垂体细胞和t细胞功能影响的机理研究[J].南京农业大学学报.2000,23：72-75
[161]Brust P, Kohler R, Brandsch M, et al. Effects of dietary beta-casomorphins on the intestinal transport of amino-acids and on plasma-insulin concentrations in rats[J]. Zoologische Jahrbucher-Abteilung Fur Allgemeine Zoologie Und Physiologie Der Tiere.1991,95:97-107
[162]凌明亮,黄仁术,严梅根,等.β酪啡肽对早期断奶仔猪生长性能及小肠形态,菌群,吸收功能的影响[J].粮食与饲料工业.2004,11：31-33
[163]周文华,陈伟华,邹思湘.饲喂β-酪啡肽对大鼠免疫功能影响的研究[J].畜牧与兽医.2002,34：13-15
[164]Kayser H, Meisel H. Stimulation of human peripheral blood lymphocytes by bioactive peptides derived from bovine milk proteins[J]. FEBS Lett.1996,383:18-20
[165]张源淑.酪蛋白酶解及其产物的阿片肽样活性研究[D].南京：南京农业大学硕士论文,1997.
[166]潘翠玲,陈伟华,邹思湘,等.β-酪啡肽-7对早期断乳仔猪免疫器官及内分泌功能的影响[J].南京农业大学学报.2003,26：67-70
[167]张源淑,邓艳,宋晓丹,等.酪啡肽及其酪蛋白水解肽对早期断奶仔猪分泌型免疫球蛋白a和细胞因子水平的影响[J].动物营养学报.2008,20：196-199
[168]吴金节,章孝荣,陶勇.β-酪啡肽对公山羊血清FSH,LH和T水平的影响[J].安徽农业大学学报.2001,28：152-155
[169]张源淑,邹思湘.乳源阿片肽活性物质对动物消化,代谢的影响[J].中国饲料.2001,13：14-21
[170]White CL, Bray GA, York DA.Intragastric beta-casomorphin(1-7) attenuates the suppression of fat intake by enterostatin[J]. Peptides.2000,21:1377-1381
[171]Dubynin VA, Asmakova LS, Sokhanenkova NI, et al. Comparative analysis of neurotropic activity exorphins--derivatives of dietary proteins[J]. Biulleten 'eksperimental' noi biologii i meditsiny.1998, 125:153-157
[172]Becker A, Grecksch G, Matthies H. Influence of beta-casomorphin derivatives on chemically and electrically induced seizures[J]. Peptides.1991,12:43-45
[173]Dubynin V, Ivleva I, Kamenskii A. The neurotropic activity of food-derived opioid peptides beta-casomorphins][J]. Usp. Fiziol. Nauk.2004,35:83-101
[174]Sakaguchi M, Murayama K, Jinsmaa Y, et al. Neurite outgrowth-stimulating activities of beta-casomorphins in neuro-2a mouse neuroblastoma cells[J]. Biosci., Biotechnol., Biochem.2003, 67:2541-2547
[175]Sakaguchi M, Koseki M, Wakamatsu M, et al. Effects of systemic administration of beta-casomorphin-5 on learning and memory in mice[J]. Eur. J. Pharmacol.2006,530:81-87
[176]Sakaguchi M, Koseki M, Wakamatsu M, et al. Effects of beta-casomorphin-5 on passive avoidance response in mice[J]. Biosci., Biotechnol., Biochem.2003,67:2501-2504
[177]宋晓丹.乳源β-酪啡肽-7降血糖作用及其机制的研究[D].南京农业大学硕士学位论文,2009.
[178]范英兰.β-酪啡肽-5对糖尿病大鼠血糖和氧化应激的影响[D].南京农业大学硕士学位论文,2010.
[179]Yin H, Miao JF, Zhang YS. Protective effect of beta-casomorphin-7 on type 1 diabetes rats induced with streptozotocin[J]. Peptides.2010,31:1725-1729
[180]Han D-N, Zhang D-H, Wang L-P, et al. Protective effect of β-casomorphin-7 on cardiomyopathy of streptozotocin-induced diabetic rats via inhibition of hyperglycemia and oxidative stress[J]. Peptides.2013,44:120-126
[181]Dubynin VA, Malinovskaya IV, Ivleva YA, et al. Delayed behavioral effects of beta-casomorphin-7 depend on age and gender of albino rat pups[J]. Bull. Exp. Biol. Med.2000,130:1031-1034
[182]Saito T. Antihypertensive peptides derived from bovine casein and whey proteins[M]. Advances in Experimental Medicine and Biology.2008,606:295-317'
[183]Sokolov OY, Kost NV, Zolotarev YA, et al. Influence of human b-casomorphin-7 on specific binding of h-3-spiperone to the 5-ht2-receptors of rat brain frontal cortex[J]. Protein Peptide Letters. 2006,13:169-170
[1]Harvey JN. Diabetic nephropathy-new drugs can help to face a growing challenge[J]. Br. Med. J. 2002,325:59-60
[2]Kanwar YS, Wada J, Sun L, et al. Diabetic nephropathy:Mechanisms of renal disease progression[J]. Exp. Biol. Med.2008,233:4-11
[3]Brantl V, Teschemacher H, Henschen A, et al. Novel opioid peptides derived from casein (beta-casomorphins). I. Isolation from bovine casein peptone[J]. Hoppe-Seyler's Z. Physiol. Chem. 1979,360:1211-1216
[4]宋晓丹,左伟勇,范英兰,等.乳源β-酪啡肽7对大鼠葡萄糖吸收的影响及其作用机制[J].世界华人消化杂志.2009,17：1947-1951
[5]Han D-N, Zhang D-H, Wang L-P, et al. Protective effect of β-casomorphin-7 on cardiomyopathy of streptozotocin-induced diabetic rats via inhibition of hyperglycemia and oxidative stress[J]. Peptides.2013,44:120-126
[6]Yin H, Miao J, Ma C, et al. Beta-casomorphin-7 cause decreasing in oxidative stress and inhibiting nf-kappab-inos-no signal pathway in pancreas of diabetes rats[J]. J. Food Sci.2012,77:C278-282
[7]Yin H, Miao J, Zhang Y. Protective effect of beta-casomorphin-7 on type 1 diabetes rats induced with streptozotocin[J]. Peptides.2010,31:1725-1729
[8]Somani R, Singhai AK, Shivgunde P, et al. Asparagus racemosus willd (liliaceae) ameliorates early diabetic nephropathy in stz induced diabetic rats[J]. Indian J. Exp. Biol.2012,50:469-475
[9]Soulis-Liparota T, Cooper M, Papazoglou D, et al. Retardation by aminoguanidine of development of albuminuria, mesangial expansion, and tissue fluorescence in streptozocin-induced diabetic rat[J]. Diabetes.1991,40:1328-1334
[10]马畅.血管紧张素转化酶2(ACE2)在糖尿病大鼠肾损伤中的作用及其机制[D].南京农业大学硕士学位论文,2010.
[11]张景云.结缔组织生长因子在糖尿病肾病发病中的作用及己酮可可碱对其表达影响的研究[D].天津医科大学博士学位论文,2007.
[12]Mankhey RW, Bhatti F, Maric C.17 beta-estradiol replacement improves renal function and pathology associated with diabetic nephropathy[J]. Am. J. Physiol-Renal.2005,288:F399-F405
[13]Ma YY, Sun D, Li J, et al. Transplantation of endothelial progenitor cells alleviates renal interstitial fibrosis in a mouse model of unilateral ureteral obstruction[J]. Life Sci.2010,86:798-807
[14]Heid CA, Stevens J, Livak KJ, et al. Real time quantitative pcr[J]. Genome Res.1996,6:986-994
[15]李鹏飞,苗晋锋,马畅,等.ACE和ACE2在自发性高血压大鼠肾脏中的表达与作用分析[J]. 南京农业大学学报.2011,34：85-88
[16]王竹,杨月欣,向雪松,等.实验大鼠血糖正常范围的估算[J].卫生研究.2010,39：133-137
[17]吕增华,张杨杨,朱玉红.肾穿刺活检六胺银染色套染masson染色方法的改良[J].临床与实验病理学杂志.2012,28：1289-1290
[18]罗灿峤,莫木琼,钟觉民.天狼星红苦味酸染色法和masson染色法在显示大鼠肾脏胶原纤维的比较应用[J].临床医学工程.2009,16：15-16
[19]Moresco RN, Sangoi MB, De Carvalho JA, et al. Diabetic nephropathy:Traditional to proteomic markers[J]. Clin. Chim. Acta.2013,421:17-30
[20]黄昕,崔磊,曹谊林.STZ诱导裸鼠糖尿病模型的建立及观察[J].组织工程与重建外科杂志.2007，3：186-188
[21]Gunnarsson R, Berne C, Hellerstrom C. Cytotoxic effects of streptozotocin and n-nitrosomethylurea on the pancreatic b cells with special regard to the role of nicotinamide-adenine dinucleotide[J]. Biochem. J.1974,140:487-494
[22]Laue C, Kaiser A, Wendl K, et al. Reversal of streptozotocin-diabetes after transplantation of piscine principal islets to nude mice[J]. Transpl P.2001;33:3504-3510
[23]Mukherjee B, Anbazhagan S, Roy A, et al. Novel implications of the potential role of selenium on antioxidant status in streptozotocin-induced diabetic mice[J]. Biomed. Pharmacother. 1998,52:89-95
[24]Kalender B, Oztiirk M, Tuncdemir M, et al. Renoprotective effects of valsartan and enalapril in stz-induced diabetes in rats[J]. Acta Histochem.2002,104:123-130
[25]宋晓丹,任欢欢,印虹,等.B-酪啡肽-7对大鼠离体小肠葡萄糖吸收的抑制效应[J].营养学报.2010：117-120
[26]宗亚峰.β酪啡肽在大鼠胃肠道内的释放,吸收和稳定特性及其对胃肠机能的影响[D].南京农业大学,2007.
[27]Schena FP, Gesualdo L. Pathogenetic mechanisms of diabetic nephropathy [J]. J. Am. Soc. Nephrol. 2005,16:S30-S33
[28]Razzaque MS, Koji T, Taguchi T, et al. In situ localization of type ⅲ and type ⅳ collagen-expressing cells in human diabetic nephropathy[J]. J Pathol.1994,174:131-138
[1]Gilbert RE, Cooper ME. The tubulointerstitium in progressive diabetic kidney disease:More than an aftermath of glomerular injury?[J]. Kidney Int.1999,56:1627-1637
[2]Nath KA. The tubulointerstitium in progressive renal disease[J]. Kidney Int.1998,54:992-994
[3]Schena FP, Gesualdo L. Pathogenetic mechanisms of diabetic nephropathy[J]. J. Am. Soc. Nephrol. 2005,16:S30-S33
[4]Iwano M, Plieth D, Danoff TM, et al. Evidence that fibroblasts derive from epithelium during tissue fibrosis[J]. J. Clin. Invest.2002,110:341-350
[5]Kalluri R, Neilson EG. Epithelial-mesenchymal transition and its implications for fibrosis[J]. J. Clin. Invest.2003,112:1776-1784
[6]Carew RM, Wang B, Kantharidis P. The role of emt in renal fibrosis[J]. Cell Tissue Res. 2012,347:103-116
[7]Forbes JM, Coughlan MT, Cooper ME. Oxidative stress as a major culprit in kidney disease in diabetes[J]. Diabetes.2008,57:1446-1454
[8]Brownlee M. Biochemistry and molecular cell biology of diabetic complications[J]. Nature. 2001,414:813-820
[9]Susztak K, Raff AC, Schiffer M, et al. Glucose-induced reactive oxygen species cause apoptosis of podocytes and podocyte depletion at the onset of diabetic nephropathy[J]. Diabetes. 2006,55:225-233
[10]Ha H, Hwang I-A, Park JH, et al. Role of reactive oxygen species in the pathogenesis of diabetic nephropathy[J]. Diabetes Res. Clin. Pract.2008,82:S42-S45
[11]Khazim K, Gorin Y, Cavaglieri RC, et al. The antioxidant silybin prevents high glucose-induced oxidative stress and podocyte injury in vitro and in vivo[J]. Am J of physiol-Renal. 2013,305:F691-700
[12]Yin H, Miao JF, Zhang YS. Protective effect of beta-casomorphin-7 on type 1 diabetes rats induced with streptozotocin[J]. Peptides.2010,31:1725-1729
[13]Han D-N, Zhang D-H, Wang L-P, et al. Protective effect of β-casomorphin-7 on cardiomyopathy of streptozotocin-induced diabetic rats via inhibition of hyperglycemia and oxidative stress[J]. Peptides.2013,44:120-126
[14]Boutet A, De Frutos CA, Maxwell PH, et al. Snail activation disrupts tissue homeostasis and induces fibrosis in the adult kidney[J]. EMBO J.2006,25:5603-5613
[15]Bhowmick NA, Ghiassi M, Bakin A, et al. Transforming growth factor-beta 1 mediates epithelial to mesenchymal transdifferentiation through a rhoa-dependent mechanism[J]. Mol. Biol. Cell.2001, 12:27-36
[16]Bienz M. Beta-catenin:A pivot between cell adhesion and wnt signalling[J]. Curr. Biol.2005, 15:R64-R67
[17]Kaimori A, Potter J, Kaimori J-y, et al. Transforming growth factor-beta 1 induces an epithelial-to-mesenchymal transition state in mouse hepatocytes in vitro[J]. J. Biol. Chem.2007, 282:22089-22101
[18]Burns WC, Twigg SM, Forbes JM, et al. Connective tissue growth factor plays an important role in advanced glycation end product-induced tubular epithelial-to-mesenchymal transition:Implications for diabetic renal disease[J]. J. Am. Soc. Nephrol.2006,17:2484-2494
[19]Yamagishi S, Matsui T. Advanced glycation end products, oxidative stress and diabetic nephropathy[J]. Oxidative Medicine and Cellular Longevity.2010,3:101-108
[20]Draper H, Hadley M. Malondialdehyde determination as index of lipid peroxidation[J]. Methods Enzymol.1990,186:421-431
[21]Gao Y, Zhang RR, Li JH, et al. Radix astragali lowers kidney oxidative stress in diabetic rats treated with insulin[J]. Endocrine.2012,42:592-598
[22]Wu D, Wen W, Qi C-L, et al. Ameliorative effect of berberine on renal damage in rats with diabetes induced by high-fat diet and streptozotocin[J]. Phytomedicine.2012,19:712-718
[23]Badid C, Desmouliere A, Babici D, et al. Interstitial expression of alpha-sma:An early marker of chronic renal allograft dysfunction[J]. Nephrol Dial Transpl.2002,17:1993-1998
[24]Zeisberg M, Kalluri R. The role of epithelial-to-mesenchymal transition in renal fibrosis[J]. J. Mol. Med-Jmm.2004,82:175-181
[25]Noh H, Oh EY, Seo JY, et al. Histone deacetylase-2 is a key regulator of diabetes- and transforming growth factor-beta 1-induced renal injury[J]. Am. J. Physiol-Renal.2009,297:F729-F739
[26]Zhang M, Liu M, Xiong M, et al. Schisandra chinensis fruit extract attenuates albuminuria and protects podocyte integrity in a mouse model of streptozotocin-induced diabetic nephropathy[J]. J. Ethnopharmacol.2012,141:111-118
[27]王予慧.氧化应激在糖尿病肾病鼠肾小管上皮细胞转分化中的作用及普罗布考干预研究[D]。中南大学硕士论文,2009
[28]Rhyu DY, Yang YQ, Ha HJ, et al. Role of reactive oxygen species in tgf-beta 1-induced mitogen-activated protein kinase activation and epithelial-mesenchymal transition in renal tubular epithelial cells[J]. J. Am. Soc. Nephrol.2005,16:667-675
[29]Gorowiec MR, Borthwick LA, Parker SM, et al. Free radical generation induces epithelial-to-mesenchymal transition in lung epithelium via a tgf-beta 1-dependent mechanism[J]. Free Radic. Biol. Med.2012,52:1024-1032
[1]Schena FP, Gesualdo L. Pathogenetic mechanisms of diabetic nephropathy[J]. J. Am. Soc. Nephrol. 2005,16:S30-S33
[2]Gurley SB, Coffman TM. The renin-angiotensin system and diabetic nephropathy[C]. Seminars in nephrology.2007;27:144-152
[3]Peach M. Renin-angiotensin system:Biochemistry and mechanisms of action[J]. Physiol. Rev. 1977,57:313-370
[4]Zatz R, Dunn BR, Meyer TW, et al. Prevention of diabetic glomerulopathy by pharmacological amelioration of glomerular capillary hypertension[J]. J. Clin. Invest.1986,77:1925
[5]Donoghue M, Hsieh F, Baronas E, et al. A novel angiotensin-converting enzyme-related carboxypeptidase (ace2) converts angiotensin i to angiotensin 1-9[J]. Circ. Res.2000,87:E1-E9
[6]Tom B, Dendorfer A, Jan Danser A. Bradykinin, angiotensin-(1-7), and ace inhibitors:How do they interact?[J]. Int J Biochem Cell B,2003,35:792-801
[7]Tikellis C, Johnston CI, Forbes JM, et al. Characterization of renal angiotensin-converting enzyme 2 in diabetic nephropathy[J]. Hypertension.2003,41:392-397
[8]王艳霞,张伟,韩东宁,等.血管紧张素转化酶2(Ace2)对大鼠肾氧化应激损伤的保护作用及其机制[J].农业生物技术学报.2011,19：881-886
[9]Turner AJ, Hooper NM. The angiotensin-converting enzyme gene family:Genomics and pharmacology[J]. Trends Pharmacol. Sci.2002,23:177-183
[10]Corvol P, Michaud A, Soubrier F, et al. Recent advances in knowledge of the structure and function of the angiotensin-i converting-enzyme[J]. J. Hypertens.1995,13:S3-S10
[11]Brown WV. Microvascular complications of diabetes mellitus:Renal protection accompanies cardiovascular protection[J]. Am J Cardiol.2008,102:10L-13L
[12]Colucci JA, Arita DY, Cunha TS, et al. Renin-angiotensin system may trigger kidney damage in nod mice[J]. J Renin-Angio-Aldo S.2011,12:15-22
[13]Hostetter TH, Troy J, Brenner B. Glomerular hemodynamics in experimental diabetes mellitus[J]. Kidney Int.1981,19:410-415
[14]Rossig L, Hermann C, Haendeler J, et al. Angiotensin ii-induced upregulation of map kinase phosphatase-3 mrna levels mediates endothelial cell apotosis[J]. Basic Res. Cardiol.2002,97:1-8
[15]Kobori H, Nangaku M, Navar LG, et al. The intrarenal renin-angiotensin system:From physiology to the pathobiology of hypertension and kidney disease[J]. Pharmacol. Rev.2007,59:251-287
[16]Mezzano SA, Ruiz-Ortega M, Egido J. Angiotensin ii and renal fibrosis[J]. Hypertension. 2001,38:635-638
[17]Yang JW, Dai CS, Liu YH. Hepatocyte growth factor gene therapy and angiotensin ii blockade synergistically attenuate renal interstitial fibrosis in mice [J]. J. Am. Soc. Nephrol.2002, 13:2464-2477
[18]Shiota A, Yamamoto K, Ohishi M, et al. Loss of ace2 accelerates time-dependent glomerular and tubulointerstitial damage in streptozotocin-induced diabetic mice [J]. Hypertens. Res.2010, 33:298-307
[19]Nadarajah R, Milagres R, Dilauro M, et al. Podocyte-specific overexpression of human angiotensin-converting enzyme 2 attenuates diabetic nephropathy in mice [J]. Kidney Int.2012, 82:292-303
[20]Wong DW, Oudit GY, Reich H, et al. Loss of angiotensin-converting enzyme-2 (ace2) accelerates diabetic kidney injury[J]. Am. J. Pathol.2007,171:438-451
[21]Qian Y-R, Guo Y, Wan H-Y, et al. Angiotensin-converting enzyme 2 attenuates the metastasis of non-small cell lung cancer through inhibition of epithelial-mesenchymal transition[J]. Oncol. Rep. 2013,29:2408-2414
[22]Oudit G, Herzenberg A, Chappell M, et al. Loss of angiotensin converting enzyme 2 (ace2) leads to the development of an age-dependent renal glomerular injury [J]. Circulation.2003,108:151-151
[23]Gwathmey TM, Pendergrass KD, Reid SD, et al. Angiotensin-(1-7)-angiotensin-converting enzyme 2 attenuates reactive oxygen species formation to angiotensin ii within the cell nucleus[J]. Hypertension.2010,55:166-171
[24]Zhong JC, Guo D, Chen CB, et al. Prevention of angiotensin ii-mediated renal oxidative stress, inflammation, and fibrosis by angiotensin-converting enzyme 2[J]. Hypertension.2011,57:314-322
[25]Ye MH, Wysocki J, Naaz P, et al. Differential expression of angiotensin converting enzyme (ace) and ace-related carboxypeptidase (ace2) in diabetic db/db mice [J]. Hypertension.2004, 43:1352-1352
[26]Ye M, Wysocki J, Naaz P, et al. Increased ace 2 and decreased ace protein in renal tubules from diabetic mice a renoprotective combination?[J]. Hypertension.2004,43:1120-1125
[27]Wysocki J, Soler MJ, Ye M, et al. Ace/ace2 expression in glomeruli from db/db mice with established nephropathy and the effect of chronic ace2 inhibition[J]. Nephrol Dial Transpl. 2007,22:268-268
[28]马畅.血管紧张素转化酶2(ACE2)在糖尿病大鼠肾损伤中的作用及其机制[D].南京农业大学硕士学位论文,2010。
[1]Paul M, Mehr AP, Kreutz R. Physiology of local renin-angiotensin systems[J]. Physiol. Rev. 2006,86:747-803
[2]Paravicini TM, Touyz RM. Redox signaling in hypertension[J]. Cardiovasc. Res.2006,71:247-258
[3]Shah SV, Baliga R, Rajapurkar M, et al. Oxidants in chronic kidney disease[J]. J. Am. Soc. Nephrol. 2007,18:16-28
[4]Wilson S. Role of oxygen-derived free radicals in acute angiotensin ⅱ--nduced hypertensive vascular disease in the rat[J]. Circ. Res.1990,66:722-734
[5]Peng ZZ, Hu GY, Shen H, et al. Fluorofenidone attenuates collagen i and transforming growth factor-beta l expression through a nicotinamide adenine dinucleotide phosphate oxidase-dependent way in nrk-52e cells[J]. Nephrology.2009,14:565-572
[6]Kawahara T, Ritsick D, Cheng G, et al. Point mutations in the proline-rich region of p22phox are dominant inhibitors of noxl-and nox2-dependent reactive oxygen generation [J]. J. Biol. Chem. 2005,280:31859-31869
[7]Okada H, Danoff TM, Kalluri R, et al. Early role of fspl in epithelial-mesenchymal transformation[J]. Am. J. Physiol-Renal.1997,273:F563-F574
[8]Yang JW, Liu YH. Dissection of key events in tubular epithelial to myofibroblast transition and its implications in renal interstitial fibrosis[J]. Am. J. Pathol.2001,159:1465-1475
[9]Yang JW, Dai CS, Liu YH. Hepatocyte growth factor gene therapy and angiotensin ii blockade synergistically attenuate renal interstitial fibrosis in mice[J]. J. Am. Soc. Nephrol.2002,13:2464-2477
[10]Burns WC, Velkoska E, Dean R, et al. Angiotensin ii mediates epithelial-to-mesenchymal transformation in tubular cells by ang 1-7/mas-l-dependent pathways[J]. Am. J. Physiol-Renal. 2010,299:F585-F593
[11]Chen JC, Chen JK, Harris RC. Angiotensin ii induces epithelial-to-mesenchymal transition in renal epithelial cells through reactive oxygen species/src/caveolin-mediated activation of an epidermal growth factor receptor-extracellular signal-regulated kinase signaling pathway[J]. Mol. Cell. Biol. 2012,32:981-991
[12]Zhou L, Xue H, Yuan P, et al. Angiotensin atl receptor activation mediates high glucose-induced epithelial-mesenchymal transition in renal proximal tubular cells[J]. Clin. Exp. Pharmacol. Physiol. 2010,37:e152-e157
[13]Mezzano SA, Ruiz-Ortega M, Egido J. Angiotensin ii and renal fibrosis[J]. Hypertension.2001, 38:635-638
[14]Jandeleit-Dahm K, Cooper ME. Hypertension and diabetes:Role of the renin-angiotensin system[J]. Endocrinol. Metab. Clin. North Am.2006,35:469-490
[15]Wang D, Chen Y, Chabrashvili T, et al. Role of oxidative stress in endothelial dysfunction and enhanced responses to angiotensin ii of afferent arterioles from rabbits infused with angiotensin ii[J]. J. Am. Soc. Nephrol.2003,14:2783-2789
[16]Zafari AM, Ushio-Fukai M, Akers M, et al. Role of nadh/nadph oxidase-derived h2o2 in angiotensin ii-induced vascular hypertrophy [J]. Hypertension.1998,32:488-495
[17]Sun L, Xiao L, Nie J, et al. P66shc mediates high-glucose and angiotensin ii-induced oxidative stress renal tubular injury via mitochondrial-dependent apoptotic pathway[J]. Am. J. Physiol-Renal. 2010,299:F1014-F1025
[18]Whittaker L, McArdle F, Jackson MJ, et al. Oxidative stress induced by hyperglycaemia and angiotensin ii in hk-2 cells[J]. Nephrol Dial Transpl.2005,20:V237-V237
[19]Chen L, LIU Be, ZHANG XI, et al. Influence of connective tissue growth factor antisense oligonucleotide on angiotensin ii-induced epithelial mesenchymal transition in hk2 cells1[J]. Acta Pharmacol Sin.2006,27:1029-1036
[20]Rodrigues-Diez R, Carvajal-Gonzalez G, Sanchez-Lopez E, et al. Pharmacological modulation of epithelial mesenchymal transition caused by angiotensin ii. Role of rock and mapk pathways[J]. Pharm. Res.2008,25:2447-2461
[21]Wolf G, Mueller E, Stahl R, et al. Angiotensin ii-induced hypertrophy of cultured murine proximal tubular cells is mediated by endogenous transforming growth factor-beta[J]. J. Clin. Invest.1993, 92:1366
[22]Song JH, Cha SH, Lee HJ, et al. Effect of low-dose dual blockade of renin-angiotensin system on urinary tgf-β in type 2 diabetic patients with advanced kidney disease[J]. Nephrol Dial Transpl. 2006,21:683-689
[23]Carvajal G, Rodriguez-Vita J, Rodrigues-Diez R, et al. Angiotensin ii activates the smad pathway during epithelial mesenchymal transdifferentiation[J]. Kidney Int.2008,74:585-595
[24]Chabrashvili T, Kitiyakara C, Blau J, et al. Effects of ang ii type 1 and 2 receptors on oxidative stress, renal nadph oxidase, and sod expression[J]. Am J Physiol-Reg I.2003,285:R117-R124
[25]Zimpelmann J, Kumar D, Levine DZ, et al. Early diabetes mellitus stimulates proximal tubule renin mrna expression in the rat[J]. Kidney Int.2000,58:2320-2330
[26]Mizuiri S, Hemmi H, Arita M, et al. Increased ace and decreased ace2 expression in kidneys from patients with iga nephropathy[J]. Nephron Clin Pract.2011,117:C57-C66
[27]Moon JY, Jeong KH, Lee SH, et al. Renal ace and ace2 expression in early diabetic rats[J]. Nephron Exp Nephrol.2008,110:E8-E16
[28]Gwathmey TM, Pendergrass KD, Reid SD, et al. Evidence that the ace2-angiotensin-(1-7) pathway counterbalances angiotensin ii-induced formation of reactive oxygen species in renal nuclei[J]. Hypertension.2008,52:E124-E125
[29]Zhong J, Oudit GY, Basu R, et al. Recombinant human ace2 attenuates pressure overload-induced pathological myocardial remodeling[J]. Can. J. Cardiol.2010,26:71d-72d
[30]Qian Y-R, Guo Y, Wan H-Y, et al. Angiotensin-converting enzyme 2 attenuates the metastasis of non-small cell lung cancer through inhibition of epithelial-mesenchymal transition[J]. Oncol. Rep. 2013,29:2408-2414
[1]黄听,崔磊,曹谊林.STZ诱导裸鼠糖尿病模型的建立及观察[J].组织工程与重建外科杂志.2007,3：186-188
[2]Gunnarsson R, Berne C, Hellerstrom C. Cytotoxic effects of streptozotocin and n-nitrosomethylurea on the pancreatic b cells with special regard to the role of nicotinamide-adenine dinucleotide[J]. Biochem. J.1974,140:487-494
[3]Laue C, Kaiser A, Wendl K, et al. Reversal of streptozotocin-diabetes after transplantation of piscine principal islets to nude mice. Transpl P.2001;33:3504-3510
[4]Mukherjee B, Anbazhagan S, Roy A, et al. Novel implications of the potential role of selenium on antioxidant status in streptozotocin-induced diabetic mice[J]. Biomed. Pharmacother.1998,52: 89-95
[5]范英兰.β-酪啡肽-5对糖尿病大鼠血糖和氧化应激的影响[D].南京农业大学硕士学位论文,2010.
[6]印虹.β-酪啡肽7和酪蛋白水解肽对糖尿病大鼠血糖和氧化应激的影响[D].南京农业大学硕士学位论文,2010.
[7]韩东宁.β-酪啡肽-7对i型糖尿病大鼠心肌损伤的干预作用及其机制[D].南京农业大学硕士学位论文,2011.
[8]马畅.血管紧张素转化酶2(ace2)在糖尿病大鼠肾损伤中的作用及其机制[D].南京农业大学硕士学位论文,2010.
[9]Salpeter SR, Greyber E, Pasternak GA, et al. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus:Systematic review and meta-analysis[J]. Arch. Intern. Med.2003,163:2594
[10]宋晓丹.乳源β-酪啡肽-7降血糖作用及其机制的研究[D].南京农业大学硕士学位论文,2009.
[11]张源淑.酪啡肽的鉴定及其对仔猪消化道功能的影响研究[D].南京农业大学博士学位论文,2004.
[12]张必武,乐国伟,施用晖,等.乳蛋白源阿片肽-β-酪啡肽[J].饲料研究.2001,6：14-15
[13]宗亚峰.β酪啡肽在大鼠胃肠道内的释放、吸收和稳定特性及其对胃肠机能的影响[D].南京农业大学博士学位论文,2007.
[14]Yin H, Miao JF, Zhang YS. Protective effect of beta-casomorphin-7 on type 1 diabetes rats induced with streptozotocin[J]. Peptides.2010,31:1725-1729
[15]Han D-N, Zhang D-H, Wang L-P, et al. Protective effect of β-casomorphin-7 on cardiomyopathy of streptozotocin-induced diabetic rats via inhibition of hyperglycemia and oxidative stress[J]. Peptides.2013,44:120-126
[16]Schena FP, Gesualdo L. Pathogenetic mechanisms of diabetic nephropathy[J]. J. Am. Soc. Nephrol. 2005,16:S30-S33
[17]Yamagishi S, Matsui T. Advanced glycation end products, oxidative stress and diabetic nephropathy [J]. Oxid Med Cellular Longev.2010,3:101-108
[18]Ha H, Hwang I-A, Park JH, et al. Role of reactive oxygen species in the pathogenesis of diabetic nephropathy [J]. Diabetes Res. Clin. Pract.2008,82:S42-S45
[19]Draper H, Hadley M. Malondialdehyde determination as index of lipid peroxidation[J]. Methods Enzymol.1990,186:421-431
[20]Gao Y, Zhang RR, Li JH, et al. Radix astragali lowers kidney oxidative stress in diabetic rats treated with insulin[J]. Endocrine.2012,42:592-598
[21]Wu D, Wen W, Qi C-L, et al. Ameliorative effect of berberine on renal damage in rats with diabetes induced by high-fat diet and streptozotocin[J]. Phytomedicine.2012,19:712-718
[22]Nath KA. The tubulointerstitium in progressive renal disease[J]. Kidney Int.1998,54:992-994
[23]Badid C, Desmouliere A, Babici D, et al. Interstitial expression of alpha-sma:An early marker of chronic renal allograft dysfunction[J]. Nephrol Dial Transpl.2002,17:1993-1998
[24]Kalluri R, Neilson EG. Epithelial-mesenchymal transition and its implications for fibrosis[J]. J. Clin. Invest.2003,112:1776-1784
[25]Noh H, Oh EY, Seo JY, et al. Histone deacetylase-2 is a key regulator of diabetes-and transforming growth factor-beta 1-induced renal injury[J]. Am. J. Physiol-Renal.2009,297:F729-F739
[26]Zhang M, Liu M, Xiong M, et al. Schisandra chinensis fruit extract attenuates albuminuria and protects podocyte integrity in a mouse model of streptozotocin-induced diabetic nephropathy [J]. J. Ethnopharmacol.2012,141:111-118
[27]Corvol P, Michaud A, Soubrier F, et al. Recent advances in knowledge of the structure and function of the angiotensin-i converting-enzyme [J]. J. Hypertens.1995,13:S3-S10
[28]Zimpelmann J, Kumar D, Levine DZ, et al. Early diabetes mellitus stimulates proximal tubule renin mrna expression in the rat[J]. Kidney Int.2000,58:2320-2330
[29]Ye MH, Wysocki J, Naaz P, et al. Differential expression of angiotensin converting enzyme (ace) and ace-related carboxypeptidase (ace2) in diabetic db/db mice[J]. Hypertension.2004,43:1352-1352
[30]Ye M, Wysocki J, Naaz P, et al. Increased ace 2 and decreased ace protein in renal tubules from diabetic mice a renoprotective combination?[J]. Hypertension.2004,43:1120-1125
[31]Paravicini TM, Touyz RM. Redox signaling in hypertension[J]. Cardiovasc. Res.2006,71:247-258
[32]Shah SV, Baliga R, Rajapurkar M, et al. Oxidants in chronic kidney disease[J]. J. Am. Soc. Nephrol. 2007,18:16-28
[33]Zafari AM, Ushio-Fukai M, Akers M, et al. Role of nadh/nadph oxidase-derived h2o2 in angiotensin ii-induced vascular hypertrophy [J]. Hypertension.1998,32:488-495
[34]Loot AE, Schreiber JG, Fisslthaler B, et al. Angiotensin ii impairs endothelial function via tyrosine phosphorylation of the endothelial nitric oxide synthase[J]. J Exp Med.2009,206:2889-2896
[35]Pueyo ME, Gonzalez W, Nicoletti A, et al. Angiotensin ii stimulates endothelial vascular cell adhesion molecule-1 via nuclear factor-κb activation induced by intracellular oxidative stress[J]. Arterioscler. Thromb. Vasc. Biol.2000,20:645-651
[36]An SJ, Boyd R, Zhu M, et al. Nadph oxidase mediates angiotensin ii-induced endothelin-1 expression in vascular adventitial fibroblasts[J]. Cardiovasc. Res.2007,75:702-709
[37]Kawahara T, Ritsick D, Cheng G, et al. Point mutations in the proline-rich region of p22phox are dominant inhibitors of noxl-and nox2-dependent reactive oxygen generation[J]. J. Biol. Chem. 2005,280:31859-31869
[38]Oudit GY, Herzenberg AM, Kassiri Z, et al. Loss of angiotensin-converting enzyme-2 leads to the late development of angiotensin ii-dependent glomerulosclerosis[J]. Am J Pathol.2006,168:1808-1820
[39]Gwathmey TM, Pendergrass KD, Reid SD, et al. Angiotensin-(1-7)-angiotensin-converting enzyme 2 attenuates reactive oxygen species formation to angiotensin ii within the cell nucleus[J]. Hypertension.2010,55:166-171
[40]Zhong J, Guo D, Chen CB, et al. Prevention of angiotensin ii-mediated renal oxidative stress, inflammation, and fibrosis by angiotensin-converting enzyme 2[J]. Hypertension.2011,57:314-322
[41]Yang JW, Dai CS, Liu YH. Hepatocyte growth factor gene therapy and angiotensin Ⅱ blockade synergistically attenuate renal interstitial fibrosis in mice[J]. J. Am. Soc. Nephrol. 2002,13:2464-2477
[2]Carew RM, Wang B, Kantharidis P. The role of emt in renal fibrosis[J]. Cell Tissue Res. 2012,347:103-116
[3]Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition[J]. J. Clin. Invest. 2009,119:1420-1428
[4]Liu YH. Epithelial to mesenchymal transition in renal fibrogenesis:Pathologic significance, molecular mechanism, and therapeutic intervention[J]. J. Am. Soc. Nephrol.2004,15:1-12
[5]Strutz F, Okada H, Lo CW, et al. Identification and characterization of a fibroblast marker:Fsp1[J]. J. Cell Biol.1995,130:393-406
[6]付平,何成奇,柳飞,等.肾纤复元胶囊延缓5/6肾切除大鼠肾衰进展机制的实验研究[J].四川大学学报：医学版.2006,37：430-433
[7]Lian Y-g, Zhou Q-g, Zhang Y-j, et al. Vegf ameliorates tubulointerstitial fibrosis in unilateral ureteral obstruction mice via inhibition of epithelial-mesenchymal transition[J]. Acta Pharmaco Sin. 2011,32:1513-1521
[8]Qi W, Chen X, Holian J, et al. Transforming growth factor-beta(1) differentially mediates fibronectin and inflammatory cytokine expression in kidney tubular cells[J]. Am. J. Physiol-Renal. 2006,291:F1070-F1077
[9]Kalluri R, Neilson EG. Epithelial-mesenchymal transition and its implications for fibrosis[J]. J. Clin. Invest.2003,112:1776-1784
[10]Iwano M, Plieth D, Danoff TM, et al. Evidence that fibroblasts derive from epithelium during tissue fibrosis[J]. J. Clin. Invest.2002,110:341-350
[11]Gomez-Alamillo C, Benito-Hernandez A, Ramos-Barron MA, et al. Analysis of urinary gene expression of epithelial-mesenchymal transition markers in kidney transplant recipients[J]. Transplant. Proc.2010,42:2886-2888
[12]Bhowmick NA, Ghiassi M, Bakin A, et al. Transforming growth factor-beta 1 mediates epithelial to mesenchymal transdifferentiation through a rhoa-dependent mechanism[J]. Mol. Biol. Cell. 2001,12:27-36
[13]Boutet A, De Frutos CA, Maxwell PH, et al. Snail activation disrupts tissue homeostasis and induces fibrosis in the adult kidney[J]. EMBO J.2006,25:5603-5613
[14]Brownlee M. Biochemistry and molecular cell biology of diabetic complications[J]. Nature. 2001,414:813-820
[15]Strutz F, Zeisberg M, Ziyadeh FN, et al. Role of basic fibroblast growth factor-2 in epithelial-mesenchymal transformation[J]. Kidney Int.2002,61:1714-1728
[16]Rastaldi MP, Ferrario F, Giardino L, et al. Epithelial-mesenchymal transition of tubular epithelial cells in human renal biopsies[J]. Kidney Int.2002,62:137-146
[17]Bienz M. Beta-catenin:A pivot between cell adhesion and wnt signalling[J]. Curr. Biol. 2005,15:R64-R67
[18]Kaimori A, Potter J, Kaimori J-y, et al. Transforming growth factor-beta 1 induces an epithelial-to-mesenchymal transition state in mouse hepatocytes in vitro[J]. J. Biol. Chem.2007,282: 22089-22101
[19]Burney BO, Kalaitzidis RG, Bakris GL. Novel therapies of diabetic nephropathy[J]. Curr. Opin. Nephrol. Hypertens.2009,18:107-111
[20]Burns WC, Twigg SM, Forbes JM, et al. Connective tissue growth factor plays an important role in advance glycation end product-induced tubular epithelial-to-mesenchymal transition:Implications for diabetic renal disease[J]. J. Am. Soc. Nephrol.2006,17:2484-2494
[21]Yang JW, Liu YH. Dissection of key events in tubular epithelial to myofibroblast transition and its implications in renal interstitial fibrosis[J]. Am. J. Pathol.2001,159:1465-1475
[22]Nath KA. The tubulointerstitium in progressive renal disease[J]. Kidney Int.1998,54:992-994
[23]Lee JM, Dedhar S, Kalluri R, et al. The epithelial-mesenchymal transition:New insights in signaling, development, and disease[J]. J. Cell Biol.2006,172:973-981
[24]Yu L, Border WA, Huang YF, et al. Tgf-beta isoforms in renal fibrogenesis[J]. Kidney Int. 2003,64:844-856
[25]Fan J-M, Ng Y-Y, Hill PA, et al. Transforming growth factor-&bgr; regulates tubular epithelial-myofibroblast transdifferentiation in vitro[J]. Kidney Int.1999,56:1455-1467
[26]Li JH, Zhu H-J, Huang XR, et al. Smad7 inhibits fibrotic effect of tgf-β on renal tubular epithelial cells by blocking smad2 activation[J]. J. Am. Soc. Nephrol.2002,13:1464-1472
[27]Phanish M, Wahab N, Colville-Nash P, et al. The differential role of smad2 and smad3 in the regulation of pro-fibrotic tgfbetal responses in human proximal-tubule epithelial cells[J]. Biochem. J.2006,393:601-607
[28]Bakin AV, Tomlinson AK, Bhowmick NA, et al. Phosphatidylinositol 3-kinase function is required for transforming growth factor beta-mediated epithelial to mesenchymal transition and cell migration[J]. J. Biol. Chem.2000,275:36803-36810
[29]Cano A, Perez-Moreno MA, Rodrigo I, et al. The transcription factor snail controls epithelial-mesenchymal transitions by repressing e-cadherin expression[J]. Nat Cell Biol.2000,2: 76-83
[30]Li Y, Yang J, Dai C, et al. Role for integrin-linked kinase in mediating tubular epithelial to mesenchymal transition and renal interstitial fibrogenesis[J]. J. Clin. Invest.2003,112:503-516
[31]Kim K, Lu ZF, Hay ED. Direct evidence for a. Role of beta-catenin/lef-1 signaling pathway in induction of emt[J]. Cell Biol. Int.2002,26:463-476
[32]Burns WC, Twigg SM, Forbes JM, et al. Connective tissue growth factor plays an important role in advanced glycation end product-induced tubular epithelial-to-mesenchymal transition:Implications for diabetic renal disease[J]. J. Am. Soc. Nephrol.2006,17:2484-2494
[33]Gupta S, Clarkson MR, Duggan J, et al. Connective tissue growth factor:Potential role in glomerulosclerosis and tubulointerstitial fibrosis[J]. Kidney Int.2000,58:1389-1399
[34]Qi W, Twigg S, Chen X, et al. Integrated actions of transforming growth factor-beta(1) and connective tissue growth factor in renal fibrosis[J]. Am. J. Physiol-Renal.2005,288:F800-F809
[35]Qi W, Chen X, Poronnik P, et al. Transforming growth factor-beta/connective tissue growth factor axis in the kidney[J]. Int. J. Biochem. Cell Biol.2008,40:9-13
[36]Wahab NA, Yevdokimova N, Weston BS, et al. Role of connective tissue growth factor in the pathogenesis of diabetic nephropathy[J]. Biochem. J.2001,359:77-87
[37]Paul M, Mehr AP, Kreutz R. Physiology of local renin-angiotensin systems[J]. Physiol. Rev.2006, 86:747-803
[38]Yang JW, Dai CS, Liu YH. Hepatocyte growth factor gene therapy and angiotensin ii blockade synergistically attenuate renal interstitial fibrosis in mice[J]. J. Am. Soc. Nephrol.2002,13: 2464-2477
[39]Rhyu DY, Yang Y, Ha H, et al. Role of reactive oxygen species in tgf-β1-induced mitogen-activated protein kinase activation and epithelial-mesenchymal transition in renal tubular epithelial cells[J]. J. Am. Soc. Nephrol.2005,16:667-675
[40]Nishikawa T, Edelstein D, Brownlee M. The missing link:A single unifying mechanism for diabetic complications[J]. Kidney Int. Suppl.2000,77:S26-30
[41]Fan JM, Huang XR, Ng YY, et al. Interleukin-1 induces tubular epithelial-myofibroblast transdifferentiation through a transforming growth factor-beta 1-dependent mechanism in vitro[J]. Am. J. Kidney Dis.2001,37:820-831
[42]Cheng SF, Lovett DH. Gelatinase a (mmp-2) is necessary and sufficient for renal tubular cell epithelial-mesenchymal transformation[J]. Am. J. Pathol.2003,162:1937-1949
[43]Zeisberg M, Hanai J, Sugimoto H, et al. Bmp-7 counteracts tgf-beta 1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury[J]. Nat. Med.2003,9: 964-968
[44]Yang JW, Liu YH. Blockage of tubular epithelial to myofibroblast transition by hepatocyte growth factor prevents renal interstitial fibrosis[J]. J. Am. Soc. Nephrol.2002,13:96-107
[45]de Laplanche E, Gouget K, Cleris G, et al. Physiological oxygenation status is required for fully differentiated phenotype in kidney cortex proximal tubules[J]. Am. J. Physiol-Renal.2006,291: F750-F760
[46]Okada H, Danoff TM, Kalluri R, et al. Early role of fspl in epithelial-mesenchymal transformation[J]. Am. J. Physiol-Renal.1997,273:F563-F574
[47]Schena FP, Gesualdo L. Pathogenetic mechanisms of diabetic nephropathy[J]. J. Am. Soc. Nephrol. 2005,16:S30-S33
[48]Gilbert RE, Cooper ME. The tubulointerstitium in progressive diabetic kidney disease:More than an aftermath of glomerular injury?[J]. Kidney Int.1999,56:1627-1637
[49]Nath KA. Tubulointerstitial changes as a major determinant in the progression of renal damage[J]. Am. J. Kidney Dis.1992,20:1-17
[50]Badid C, Desmouliere A, Babici D, et al. Interstitial expression of alpha-sma:An early marker of chronic renal allograft dysfunction[J]. Nephrol Dial Transpl.2002,17:1993-1998
[51]Peinado H, Quintanilla M, Cano A. Transforming growth factor beta-1 induces snail transcription factor in epithelial cell lines-mechanisms for epithelial mesenchymal transitions [J]. J. Biol. Chem. 2003,278:21113-21123
[52]Burns WC, Kantharidis P, Thomas MC. The role of tubular epithelial-mesenchymal transition in progressive kidney disease[J]. Cells Tissues Organs.2007,185:222-231
[53]Yamaguchi Y, Iwano M, Suzuki D, et al. Epithelial-mesenchymal transition as a potential explanation for podocyte depletion in diabetic nephropathy[J]. Am. J. Kidney Dis.2009,54:653-664
[54]Mauer M, Zinman B, Gardiner R, et al. Renal and retinal effects of enalapril and losartan in type 1 diabetes[J]. N. Engl. J. Med.2009,361:40-51
[55]Halawa B. Combination therapy in primary hypertension[J]. Polski merkuriusz lekarski:organ Polskiego Towarzystwa Lekarskiego.1998,4:35-38
[56]Hill C, Flyvbjerg A, Rasch R, et al. Transforming growth factor-beta 2 antibody attenuates fibrosis in the experimental diabetic rat kidney[J]. J. Endocrinol.2001,170:647-651
[57]Yokoi H, Mukoyama M, Nagae T, et al. Reduction in connective tissue growth factor by antisense treatment ameliorates renal tubulointerstitial fibrosis[J]. J. Am. Soc. Nephrol.2004,15:1430-1440
[58]Zeisberg M, Duffield JS. Resolved:Emt produces fibroblasts in the kidney[J]. J. Am. Soc. Nephrol. 2010,21:1247-1253
[59]Yang J, Dai C, Liu Y. Systemic administration of naked plasmid encoding hepatocyte growth factor ameliorates chronic renal fibrosis in mice[J]. Gene Ther.2001,8:1470-1479
[60]Hills CE, Brunskill NJ. Cellular and physiological effects of c-peptide[J]. Clin. Sci. 2009,116:565-574
[61]Kellner D, Chen J, Richardson I, et al. Angiotensin receptor blockade decreases fibrosis and fibroblast expression in a rat model of unilateral ureteral obstruction[J]. J Urology.2006,176: 806-812
[62]Duan S-B, Liu G-L, Wang Y-H, et al. Epithelial-to-mesenchymal transdifferentiation of renal tubular epithelial cell mediated by oxidative stress and intervention effect of probucol in diabetic nephropathy rats[J]. Ren. Fail.2012,34:1244-1251
[63]He W, Kang YS, Dai C, et al. Blockade of wnt/beta-catenin signaling by paricalcitol ameliorates proteinuria and kidney injury[J]. J. Am. Soc. Nephrol.2011,22:90-103
[64]Reese S, Vidyasagar A, Jacobson L, et al. The pin 1 inhibitor juglone attenuates kidney fibrogenesis via pin 1-independent mechanisms in the unilateral ureteral occlusion model[J]. Fibrogenesis & tissue repair.2010,3:1-1
[65]Aresu L, Benali S, Garbisa S, et al. Matrix metalloproteinases and their role in the renal epithelial mesenchymal transition[J]. Histol. Histopathol.2011,26:307-313
[66]Packham DK, Alves TP, Dwyer JP, et al. Relative incidence of esrd versus cardiovascular mortality in proteinuric type 2 diabetes and nephropathy:Results from the diametric (diabetes mellitus treatment for renal insufficiency consortium) database[J]. Am. J. Kidney Dis.2012,59:75-83
[67]Parving H-H. Diabetic nephropathy:Prevention and treatment[J]. Kidney Int.2001,60:2041-2055
[68]Brownlee M. The pathobiology of diabetic complications a unifying mechanism[J]. Diabetes.2005, 54:1615-1625
[69]Hakim FA, Pflueger A. Role of oxidative stress in diabetic kidney disease[J]. Medical science monitor:international medical journal of experimental and clinical research.2010,16:RA37
[70]Ruster C, Wolf G. Renin-angiotensin-aldosterone system and progression of renal disease[J]. J. Am. Soc. Nephrol.2006,17:2985-2991
[71]Kim S-M, Kim Y-G, Jeong K-H, et al. Angiotensin ii-induced mitochondrial nox4 is a major endogenous source of oxidative stress in kidney tubular cells[J]. Plos One.2012,7:e39739-e39739
[72]Whiting DR, Guariguata L, Weil C, et al. Idf diabetes atlas:Global estimates of the prevalence of diabetes for 2011 and 2030[J]. Diabetes Res. Clin. Pract.2011,94:311-321
[73]Fioretto P, Mauer M. Histopathology of diabetic nephropathy[C]. Seminars in nephrology. 2007;27:195-207
[74]Remuzzi G, Schieppati A, Ruggenenti P. Nephropathy in patients with type 2 diabetes[J]. N. Engl. J. Med.2002,346:1145-1151
[75]Galle J. Oxidative stress in chronic renal failure[J]. Nephrol Dial Transpl.2001,16:2135-2137
[76]Nishikawa T, Edelstein D, Du XL, et al. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage[J]. Nature.2000,404:787-790
[77]Asaba K, Tojo A, Onozato ML, et al. Effects of nadph oxidase inhibitor in diabetic nephropathy[J]. Kidney Int.2005,67:1890-1898
[78]Kang S-W, Natarajan R, Shahed A, et al. Role of 12-lipoxygenase in the stimulation of p38 mitogen-activated protein kinase and collagen a5 (iv) in experimental diabetic nephropathy and in glucose-stimulated podocytes[J]. J. Am. Soc. Nephrol.2003,14:3178-3187
[79]Kanwar YS, Wada J, Sun L, et al. Diabetic nephropathy:Mechanisms of renal disease progression[J]. Exp. Biol. Med.2008,233:4-11
[80]Lehmann R, Schleicher ED. Molecular mechanism of diabetic nephropathy [J]. Clin. Chim. Acta. 2000,297:135-144
[81]Yard B, Kahlert S, Engelleiter R, et al. Decreased glomerular expression of agrin in diabetic nephropathy and podocytes, cultured in high glucose medium[J]. Exp. Nephrol.2001,9:214-222
[82]Susztak K, Raff AC, Schiffer M, et al. Glucose-induced reactive oxygen species cause apoptosis of podocytes and podocyte depletion at the onset of diabetic nephropathy [J]. Diabetes.2006,55: 225-233
[83]Fukami K, Ueda S, Yamagishi S-i, et al. Ages activate mesangial tgf-β-smad signaling via an angiotensin ii type i receptor interaction[J]. Kidney Int.2004,66:2137-2147
[84]Liu Y. Epithelial to mesenchymal transition in renal fibrogenesis:Pathologic significance, molecular mechanism, and therapeutic intervention[J]. J. Am. Soc. Nephrol.2004,15:1-12
[85]Ha H, Yu MR, Choi YJ, et al. Role of high glucose-induced nuclear factor-κb activation in monocyte chemoattractant protein-1 expression by mesangial cells[J]. J. Am. Soc. Nephrol.2002,13: 894-902
[86]HA H, LEE HB. Reactive oxygen species amplify glucose signalling in renal cells cultured under high glucose and in diabetic kidney[J]. Nephrology.2005,10:S7-S10
[87]Seghieri G, Di Simplicio P, Anichini R, et al. Platelet antioxidant enzymes in insulin-dependent diabetes mellitus[J]. Clin. Chim. Acta.2001,309:19-23
[88]Fujita H, Fujishima H, Chida S, et al. Reduction of renal superoxide dismutase in progressive diabetic nephropathy [J]. J. Am. Soc. Nephrol.2009,20:1303-1313
[89]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. 2001,50:2114-2125
[90]Saklayen MG, Yap J, Vallyathan V. Effect of month-long treatment with oral n-acetylcysteine on the oxidative stress and proteinuria in patients with diabetic nephropathy:A pilot study[J]. J. Investig. Med.2010,58:28-31
[91]Turner AJ, Hooper NM. The angiotensin-converting enzyme gene family:Genomics and pharmacology[J]. Trends Pharmacol. Sci.2002,23:177-183
[92]Rosivall L. Intrarenal renin-angiotensin system[J]. Mol. Cell. Endocrinol.2009,302:185-192
[93]Zaman MA, Oparil S, Calhoun DA. Drugs targeting the renin-angiotensin-aldosterone system[J]. Nat Rev Drug Discov.2002,1:621-636
[94]Corvol P, Michaud A, Soubrier F, et al. Recent advances in knowledge of the structure and function of the angiotensin-i converting-enzyme[J]. J. Hypertens.1995,13:S3-S10
[95]Donoghue M, Hsieh F, Baronas E, et al. A novel angiotensin-converting enzyme-related carboxypeptidase (ace2) converts angiotensin i to angiotensin 1-9[J]. Circ. Res.2000,87:E1-E9
[96]Rice GI, Thomas DA, Grant PJ, et al. Evaluation of angiotensin-converting enzyme (ace), its homologue ace2 and neprilysin in angiotensin peptide metabolism[J]. Biochem. J.2004,383:45-51
[97]Tipnis SR, Hooper NM, Hyde R, et al. A human homolog of angiotensin-converting enzyme-cloning and functional expression as a captopril-insensitive carboxypeptidase[J]. J. Biol. Chem. 2000,275:33238-33243
[98]Santos RAS, Ferreira AJ, Pinheiro SVB, et al. Angiotensin-(1-7) and its receptor as a potential targets for new cardiovascular drugs[J]. Expert Opin InvDrug.2005,14:1019-1031
[99]Chappel MC, Ferrario CM. Ace and ace2:Their role to balance the expression of angiotensin ii and angiotensin-(1-7)[J]. Kidney Int.2006,70:8-10
[100]Bader M, Ganten D. Update on tissue renin-angiotensin systems[J]. J Mol Medi.2008,86:615-621
[101]Ganten D, Minnich JL, Grenger P, et al. Angiotensin-forming enzyme in brain tissue[J]. Science. 1971,173:64-65
[102]Lavoie JL, Sigmund CD. Minireview:Overview of the renin-angiotensin system-an endocrine and paracrine system[J]. Endocrinology.2003,144:2179-2183
[103]Carey RM, Siragy HM. Newly recognized components of the renin-angiotensin system:Potential roles in cardiovascular and renal regulation[J]. Endocr. Rev.2003,24:261-271
[104]Berry C, Touyz R, Dominiczak A, et al. Angiotensin receptors:Signaling, vascular pathophysiology, and interactions with ceramide[J]. Am J Physiol-C.2001,281:H2337-H2365
[105]Miyata N, Park F, Li XF, et al. Distribution of angiotensin atl and at2 receptor subtypes in the rat kidney[J]. Am. J. Physiol-Renal.1999,277:F437-F446
[106]Gembardt F, Sterner-Kock A, Imboden H, et al. Organ-specific distribution of ace2 mrna and correlating peptidase activity in rodents[J]. Peptides.2005,26:1270-1277
[107]Bader M. Ace2, angiotensin-(1-7), and mas:The other side of the coin[J]. Pflug Arch Eur J Phy. 2013,465:79-85
[108]Zimpelmann J, Kumar D, Levine DZ, et al. Early diabetes mellitus stimulates proximal tubule renin mrna expression in the rat[J]. Kidney Int.2000,58:2320-2330
[109]Hostetter TH, Troy J, Brenner B. Glomerular hemodynamics in experimental diabetes mellitus[J]. Kidney Int.1981,19:410-415
[110]Rossig L, Hermann C, Haendeler J, et al. Angiotensin ii-induced upregulation of map kinase phosphatase-3 mrna levels mediates endothelial cell apotosis[J]. Basic Res. Cardiol.2002,97:1-8
[111]Kobori H, Nangaku M, Navar LG, et al. The intrarenal renin-angiotensin system:From physiology to the pathobiology of hypertension and kidney disease[J]. Pharmacol. Rev.2007,59:251-287
[112]Mezzano SA, Ruiz-Ortega M, Egido J. Angiotensin ii and renal fibrosis[J]. Hypertension. 2001,38:635-638
[113]Kagami S, Border WA, Miller DE, et al. Angiotensin ii stimulates extracellular matrix protein synthesis through induction of transforming growth factor-beta expression in rat glomerular mesangial cells[J]. J. Clin. Invest.1994,93:2431
[114]Barnett AH, Bain SC, Bouter P, et al. Angiotensin-receptor blockade versus converting-enzyme inhibition in type 2 diabetes and nephropathy[J]. N. Engl. J. Med.2004,351:1952-1961
[115]Ye MH, Wysocki J, Naaz P, et al. Differential expression of angiotensin converting enzyme (ace) and ace-related carboxypeptidase (ace2) in diabetic db/db mice[J]. Hypertension.2004,43: 1352-1352
[116]Wysocki J, Ye MH, Soler MJ, et al. Ace and ace2 activity in diabetic mice[J]. Diabetes. 2006,55:2132-2139
[117]Tikellis C, Johnston CI, Forbes JM, et al. Characterization of renal angiotensin-converting enzyme 2 in diabetic nephropathy[J]. Hypertension.2003,41:392-397
[118]Mizuiri S, Hemmi H, Arita M, et al. Expression of ace and ace2 in individuals with diabetic kidney disease and healthy controls[J]. Am. J. Kidney Dis.2008,51:613-623
[119]Ye M, Wysocki J, William J, et al. Glomerular localization and expression of angiotensin-converting enzyme 2 and angiotensin-converting enzyme:Implications for albuminuria in diabetes[J]. J. Am. Soc. Nephrol.2006,17:3067-3075
[120]Liu CX, Hu Q, Wang Y, et al. Angiotensin-converting enzyme (ace) 2 overexpression ameliorates glomerular injury in a rat model of diabetic nephropathy:A comparison with ace inhibition[J]. Mol. Med.2011,17:59-69
[121]Soler MJ, Wysocki J, Ye M, et al. Ace2 inhibition worsens glomerular injury in association with increased ace expression in streptozotocin-induced diabetic mice[J]. Kidney Int.2007,72:614-623
[122]Shiota A, Yamamoto K, Ohishi M, et al. Loss of ace2 accelerates time-dependent glomerular and tubulointerstitial damage in streptozotocin-induced diabetic mice[J]. Hypertens. Res.2010,33: 298-307
[123]Nadarajah R, Milagres R, Dilauro M, et al. Podocyte-specific overexpression of human angiotensin-converting enzyme 2 attenuates diabetic nephropathy in mice[J]. Kidney Int.2012,82: 292-303
[124]Singh T, Singh K, Sharma PL. Ameliorative potential of angiotensin(1-7)/mas receptor axis in streptozotocin-induced diabetic nephropathy in rats[J]. Methods Find. Exp. Clin. Pharmacol.2010, 32:19-25
[125]Botelho-Santos GA, Bader M, Alenina N, et al. Altered regional blood flow distribution in mas-deficient mice[J]. Therapeutic advances in cardiovascular disease.2012,6:201-211
[126]Shao Y, He M, Zhou L, et al. Chronic angiotensin (1-7) injection accelerates stz-induced diabetic renal injuryl[J]. Acta Pharmacol Sin.2008,29:829-837
[127]Jandeleit-Dahm K, Cooper ME. Hypertension and diabetes:Role of the renin-angiotensin system[J]. Endocrinol. Metab. Clin. North Am.2006,35:469-490
[128]Paravicini TM, Touyz RM. Redox signaling in hypertension[J]. Cardiovasc. Res.2006,71:247-258
[129]Shah SV, Baliga R, Rajapurkar M, et al. Oxidants in chronic kidney disease[J]. J. Am. Soc. Nephrol.2007,18:16-28
[130]Wilson S. Role of oxygen-derived free radicals in acute angiotensin ii--induced hypertensive vascular disease in the rat[J]. Circ. Res.1990,66:722-734
[131]Wang D, Chen Y, Chabrashvili T, et al. Role of oxidative stress in endothelial dysfunction and enhanced responses to angiotensin ii of afferent arterioles from rabbits infused with angiotensin ii[J]. J. Am. Soc. Nephrol.2003,14:2783-2789
[132]Zafari AM, Ushio-Fukai M, Akers M, et al. Role of nadh/nadph oxidase-derived h2o2 in angiotensin ii-induced vascular hypertrophy [J]. Hypertension.1998,32:488-495
[133]Loot AE, Schreiber JG, Fisslthaler B, et al. Angiotensin ii impairs endothelial function via tyrosine phosphorylation of the endothelial nitric oxide synthase[J]. J Exp Med.2009,206:2889-2896
[134]Pueyo ME, Gonzalez W, Nicoletti A, et al. Angiotensin ii stimulates endothelial vascular cell adhesion molecule-1 via nuclear factor-κb activation induced by intracellular oxidative stress[J]. Arterioscler. Thromb. Vasc. Biol.2000,20:645-651
[135]An SJ, Boyd R, Zhu M, et al. Nadph oxidase mediates angiotensin ii-induced endothelin-1 expression in vascular adventitial fibroblasts[J]. Cardiovasc. Res.2007,75:702-709
[136]Kawahara T, Ritsick D, Cheng G, et al. Point mutations in the proline-rich region of p22phox are dominant inhibitors of noxl-and nox2-dependent reactive oxygen generation[J]. J. Biol. Chem. 2005,280:31859-31869
[137]Oudit GY, Herzenberg AM, Kassiri Z, et al. Loss of angiotensin-converting enzyme-2 leads to the late development of angiotensin ii-dependent glomerulosclerosis[J]. Am J Pathol.2006,168: 1808-1820
[138]Gwathmey TM, Pendergrass KD, Reid SD, et al. Angiotensin-(1-7)-angiotensin-converting enzyme 2 attenuates reactive oxygen species formation to angiotensin ii within the cell nucleus[J]. Hypertension.2010,55:166-171
[139]Zhong J, Guo D, Chen CB, et al. Prevention of angiotensin ⅱ-mediated renal oxidative stress, inflammation, and fibrosis by angiotensin-converting enzyme 2[J]. Hypertension.2011,57:314-322
[140]Giani JF, Burghi V, Veiras LC, et al. Angiotensin-(1-7) attenuates diabetic nephropathy in zucker diabetic fatty rats[J]. Am. J. Physiol-Renal.2012,302:F1606-F1615
[141]Benter IF, Yousif MH, Dhaunsi GS, et al. Angiotensin-(1-7) prevents activation of nadph oxidase and renal vascular dysfunction in diabetic hypertensive rats[J]. Am. J. Nephrol.2007,28:25-33
[142]Moon J-Y, Tanimoto M, Gohda T, et al. Attenuating effect of angiotensin-(1-7) on angiotensin ⅱ-mediated nad (p) h oxidase activation in type 2 diabetic nephropathy of kk-ay/ta mice[J]. Am. J. Physiol-Renal.2011,300:F1271-F1282
[143]Gonzales S, Noriega GO, Tomaro MaL, et al. Angiotensin-(1-7) stimulates oxidative stress in rat kidney[J]. Regul. Pept.2002,106:67-70
[144]Shao Y, He M, Zhou L, et al. Chronic angiotensin (1-7) injection accelerates stz-induced diabetic renal injury[J]. Acta Pharmacol Sin.2008,29:829-837
[145]Eigel W, Butler J, Ernstrom C, et al. Nomenclature of proteins of cow's milk:Fifth revision[J]. J. Dairy Sci.1984,67:1599-1631
[146]Ostersen S, Foldager J, Hermansen JE. Effects of stage of lactation, milk protein genotype and body condition at calving on protein composition and renneting properties of bovine milk[J]. J. Dairy Res.1997,64:207-219
[147]Brantl V, Teschemacher H, Henschen A, et al. Novel opioid peptides derived from casein (beta-casomorphins). I. Isolation from bovine casein peptone[J]. Hoppe. Seylers Z. Physiol. Chem. 1979,360:1211-1216
[148]Bradshaw J, White D. Identification of a major n-glycosylated protein of rabbit mammary gland and its appearance during development in vivo[J]. Int J Biochem.1985,17:175-185
[149]Mann D, Fraser H. The neonatal period:A critical interval in male primate development[J]. J. Endocrinol.1996,149:191-197
[150]宗亚峰.β酪啡肽在大鼠胃肠道内的释放、吸收和稳定特性及其对胃肠机能的影响[D].南京农业大学博士学位论文,2007.
[151]Schlimme E, Meisel H. Bioactive peptides derived from milk proteins. Structural, physiological and analytical aspects[J]. Food/Nahrung.1995,39:1-20
[152]Meisel H. Chemical characterization and opioid activity of an exorphin isolated from invivo digests of casein[J]. FEBS Lett.1986,196:223-227
[153]Kreil G, Umbach M, Brantl V, et al. Studies of the enzymatic degradation of β-casomorphins[J]. Life Sci.1983,33:137-140
[154]Kaminski S, Cieslinska A, Kostyra E. Polymorphism of bovine beta-casein and its potential effect on human health[J]. J Appl Genet.2007,48:189-198
[155]Froetschel M. Bioactive peptides in digesta that regulate gastrointestinal function and intake[J]. J. Anim. Sci.1996,74:2500-2508
[156]Hautefeuille M, Brantl V, Dumontier AM, et al. Beta-casomorphin derivatives decrease short-circuit current in rabbit ileum[J]. Gastroenterology.1985,88:1414-1414
[157]Schusdziarra V, Schick A, de la Fuente A, et al. Effect of beta-casomorphins and analogs on insulin release in dogs[J]. Endocrinology.1983,112:885-889
[158]Kil SJ, Froetschel MA. Involvement of opioid-peptides from casein on reticular motility and digesta passage in steers[J]. J. Dairy Sci.1994,77:111-123
[159]Morley JE, Levine A, Yamada T, et al. Effect of exorphins on gastrointestinal function, hormonal release, and appetite[J]. Gastroenterology.1983,84:1517-1523
[160]谈寅飞,邹思湘,陈伟华.β-酪啡肽-7对仔猪胃泌素分泌,垂体细胞和t细胞功能影响的机理研究[J].南京农业大学学报.2000,23：72-75
[161]Brust P, Kohler R, Brandsch M, et al. Effects of dietary beta-casomorphins on the intestinal transport of amino-acids and on plasma-insulin concentrations in rats[J]. Zoologische Jahrbucher-Abteilung Fur Allgemeine Zoologie Und Physiologie Der Tiere.1991,95:97-107
[162]凌明亮,黄仁术,严梅根,等.β酪啡肽对早期断奶仔猪生长性能及小肠形态,菌群,吸收功能的影响[J].粮食与饲料工业.2004,11：31-33
[163]周文华,陈伟华,邹思湘.饲喂β-酪啡肽对大鼠免疫功能影响的研究[J].畜牧与兽医.2002,34：13-15
[164]Kayser H, Meisel H. Stimulation of human peripheral blood lymphocytes by bioactive peptides derived from bovine milk proteins[J]. FEBS Lett.1996,383:18-20
[165]张源淑.酪蛋白酶解及其产物的阿片肽样活性研究[D].南京：南京农业大学硕士论文,1997.
[166]潘翠玲,陈伟华,邹思湘,等.β-酪啡肽-7对早期断乳仔猪免疫器官及内分泌功能的影响[J].南京农业大学学报.2003,26：67-70
[167]张源淑,邓艳,宋晓丹,等.酪啡肽及其酪蛋白水解肽对早期断奶仔猪分泌型免疫球蛋白a和细胞因子水平的影响[J].动物营养学报.2008,20：196-199
[168]吴金节,章孝荣,陶勇.β-酪啡肽对公山羊血清FSH,LH和T水平的影响[J].安徽农业大学学报.2001,28：152-155
[169]张源淑,邹思湘.乳源阿片肽活性物质对动物消化,代谢的影响[J].中国饲料.2001,13：14-21
[170]White CL, Bray GA, York DA.Intragastric beta-casomorphin(1-7) attenuates the suppression of fat intake by enterostatin[J]. Peptides.2000,21:1377-1381
[171]Dubynin VA, Asmakova LS, Sokhanenkova NI, et al. Comparative analysis of neurotropic activity exorphins--derivatives of dietary proteins[J]. Biulleten 'eksperimental' noi biologii i meditsiny.1998, 125:153-157
[172]Becker A, Grecksch G, Matthies H. Influence of beta-casomorphin derivatives on chemically and electrically induced seizures[J]. Peptides.1991,12:43-45
[173]Dubynin V, Ivleva I, Kamenskii A. The neurotropic activity of food-derived opioid peptides beta-casomorphins][J]. Usp. Fiziol. Nauk.2004,35:83-101
[174]Sakaguchi M, Murayama K, Jinsmaa Y, et al. Neurite outgrowth-stimulating activities of beta-casomorphins in neuro-2a mouse neuroblastoma cells[J]. Biosci., Biotechnol., Biochem.2003, 67:2541-2547
[175]Sakaguchi M, Koseki M, Wakamatsu M, et al. Effects of systemic administration of beta-casomorphin-5 on learning and memory in mice[J]. Eur. J. Pharmacol.2006,530:81-87
[176]Sakaguchi M, Koseki M, Wakamatsu M, et al. Effects of beta-casomorphin-5 on passive avoidance response in mice[J]. Biosci., Biotechnol., Biochem.2003,67:2501-2504
[177]宋晓丹.乳源β-酪啡肽-7降血糖作用及其机制的研究[D].南京农业大学硕士学位论文,2009.
[178]范英兰.β-酪啡肽-5对糖尿病大鼠血糖和氧化应激的影响[D].南京农业大学硕士学位论文,2010.
[179]Yin H, Miao JF, Zhang YS. Protective effect of beta-casomorphin-7 on type 1 diabetes rats induced with streptozotocin[J]. Peptides.2010,31:1725-1729
[180]Han D-N, Zhang D-H, Wang L-P, et al. Protective effect of β-casomorphin-7 on cardiomyopathy of streptozotocin-induced diabetic rats via inhibition of hyperglycemia and oxidative stress[J]. Peptides.2013,44:120-126
[181]Dubynin VA, Malinovskaya IV, Ivleva YA, et al. Delayed behavioral effects of beta-casomorphin-7 depend on age and gender of albino rat pups[J]. Bull. Exp. Biol. Med.2000,130:1031-1034
[182]Saito T. Antihypertensive peptides derived from bovine casein and whey proteins[M]. Advances in Experimental Medicine and Biology.2008,606:295-317'
[183]Sokolov OY, Kost NV, Zolotarev YA, et al. Influence of human b-casomorphin-7 on specific binding of h-3-spiperone to the 5-ht2-receptors of rat brain frontal cortex[J]. Protein Peptide Letters. 2006,13:169-170
[1]Harvey JN. Diabetic nephropathy-new drugs can help to face a growing challenge[J]. Br. Med. J. 2002,325:59-60
[2]Kanwar YS, Wada J, Sun L, et al. Diabetic nephropathy:Mechanisms of renal disease progression[J]. Exp. Biol. Med.2008,233:4-11
[3]Brantl V, Teschemacher H, Henschen A, et al. Novel opioid peptides derived from casein (beta-casomorphins). I. Isolation from bovine casein peptone[J]. Hoppe-Seyler's Z. Physiol. Chem. 1979,360:1211-1216
[4]宋晓丹,左伟勇,范英兰,等.乳源β-酪啡肽7对大鼠葡萄糖吸收的影响及其作用机制[J].世界华人消化杂志.2009,17：1947-1951
[5]Han D-N, Zhang D-H, Wang L-P, et al. Protective effect of β-casomorphin-7 on cardiomyopathy of streptozotocin-induced diabetic rats via inhibition of hyperglycemia and oxidative stress[J]. Peptides.2013,44:120-126
[6]Yin H, Miao J, Ma C, et al. Beta-casomorphin-7 cause decreasing in oxidative stress and inhibiting nf-kappab-inos-no signal pathway in pancreas of diabetes rats[J]. J. Food Sci.2012,77:C278-282
[7]Yin H, Miao J, Zhang Y. Protective effect of beta-casomorphin-7 on type 1 diabetes rats induced with streptozotocin[J]. Peptides.2010,31:1725-1729
[8]Somani R, Singhai AK, Shivgunde P, et al. Asparagus racemosus willd (liliaceae) ameliorates early diabetic nephropathy in stz induced diabetic rats[J]. Indian J. Exp. Biol.2012,50:469-475
[9]Soulis-Liparota T, Cooper M, Papazoglou D, et al. Retardation by aminoguanidine of development of albuminuria, mesangial expansion, and tissue fluorescence in streptozocin-induced diabetic rat[J]. Diabetes.1991,40:1328-1334
[10]马畅.血管紧张素转化酶2(ACE2)在糖尿病大鼠肾损伤中的作用及其机制[D].南京农业大学硕士学位论文,2010.
[11]张景云.结缔组织生长因子在糖尿病肾病发病中的作用及己酮可可碱对其表达影响的研究[D].天津医科大学博士学位论文,2007.
[12]Mankhey RW, Bhatti F, Maric C.17 beta-estradiol replacement improves renal function and pathology associated with diabetic nephropathy[J]. Am. J. Physiol-Renal.2005,288:F399-F405
[13]Ma YY, Sun D, Li J, et al. Transplantation of endothelial progenitor cells alleviates renal interstitial fibrosis in a mouse model of unilateral ureteral obstruction[J]. Life Sci.2010,86:798-807
[14]Heid CA, Stevens J, Livak KJ, et al. Real time quantitative pcr[J]. Genome Res.1996,6:986-994
[15]李鹏飞,苗晋锋,马畅,等.ACE和ACE2在自发性高血压大鼠肾脏中的表达与作用分析[J]. 南京农业大学学报.2011,34：85-88
[16]王竹,杨月欣,向雪松,等.实验大鼠血糖正常范围的估算[J].卫生研究.2010,39：133-137
[17]吕增华,张杨杨,朱玉红.肾穿刺活检六胺银染色套染masson染色方法的改良[J].临床与实验病理学杂志.2012,28：1289-1290
[18]罗灿峤,莫木琼,钟觉民.天狼星红苦味酸染色法和masson染色法在显示大鼠肾脏胶原纤维的比较应用[J].临床医学工程.2009,16：15-16
[19]Moresco RN, Sangoi MB, De Carvalho JA, et al. Diabetic nephropathy:Traditional to proteomic markers[J]. Clin. Chim. Acta.2013,421:17-30
[20]黄昕,崔磊,曹谊林.STZ诱导裸鼠糖尿病模型的建立及观察[J].组织工程与重建外科杂志.2007，3：186-188
[21]Gunnarsson R, Berne C, Hellerstrom C. Cytotoxic effects of streptozotocin and n-nitrosomethylurea on the pancreatic b cells with special regard to the role of nicotinamide-adenine dinucleotide[J]. Biochem. J.1974,140:487-494
[22]Laue C, Kaiser A, Wendl K, et al. Reversal of streptozotocin-diabetes after transplantation of piscine principal islets to nude mice[J]. Transpl P.2001;33:3504-3510
[23]Mukherjee B, Anbazhagan S, Roy A, et al. Novel implications of the potential role of selenium on antioxidant status in streptozotocin-induced diabetic mice[J]. Biomed. Pharmacother. 1998,52:89-95
[24]Kalender B, Oztiirk M, Tuncdemir M, et al. Renoprotective effects of valsartan and enalapril in stz-induced diabetes in rats[J]. Acta Histochem.2002,104:123-130
[25]宋晓丹,任欢欢,印虹,等.B-酪啡肽-7对大鼠离体小肠葡萄糖吸收的抑制效应[J].营养学报.2010：117-120
[26]宗亚峰.β酪啡肽在大鼠胃肠道内的释放,吸收和稳定特性及其对胃肠机能的影响[D].南京农业大学,2007.
[27]Schena FP, Gesualdo L. Pathogenetic mechanisms of diabetic nephropathy [J]. J. Am. Soc. Nephrol. 2005,16:S30-S33
[28]Razzaque MS, Koji T, Taguchi T, et al. In situ localization of type ⅲ and type ⅳ collagen-expressing cells in human diabetic nephropathy[J]. J Pathol.1994,174:131-138
[1]Gilbert RE, Cooper ME. The tubulointerstitium in progressive diabetic kidney disease:More than an aftermath of glomerular injury?[J]. Kidney Int.1999,56:1627-1637
[2]Nath KA. The tubulointerstitium in progressive renal disease[J]. Kidney Int.1998,54:992-994
[3]Schena FP, Gesualdo L. Pathogenetic mechanisms of diabetic nephropathy[J]. J. Am. Soc. Nephrol. 2005,16:S30-S33
[4]Iwano M, Plieth D, Danoff TM, et al. Evidence that fibroblasts derive from epithelium during tissue fibrosis[J]. J. Clin. Invest.2002,110:341-350
[5]Kalluri R, Neilson EG. Epithelial-mesenchymal transition and its implications for fibrosis[J]. J. Clin. Invest.2003,112:1776-1784
[6]Carew RM, Wang B, Kantharidis P. The role of emt in renal fibrosis[J]. Cell Tissue Res. 2012,347:103-116
[7]Forbes JM, Coughlan MT, Cooper ME. Oxidative stress as a major culprit in kidney disease in diabetes[J]. Diabetes.2008,57:1446-1454
[8]Brownlee M. Biochemistry and molecular cell biology of diabetic complications[J]. Nature. 2001,414:813-820
[9]Susztak K, Raff AC, Schiffer M, et al. Glucose-induced reactive oxygen species cause apoptosis of podocytes and podocyte depletion at the onset of diabetic nephropathy[J]. Diabetes. 2006,55:225-233
[10]Ha H, Hwang I-A, Park JH, et al. Role of reactive oxygen species in the pathogenesis of diabetic nephropathy[J]. Diabetes Res. Clin. Pract.2008,82:S42-S45
[11]Khazim K, Gorin Y, Cavaglieri RC, et al. The antioxidant silybin prevents high glucose-induced oxidative stress and podocyte injury in vitro and in vivo[J]. Am J of physiol-Renal. 2013,305:F691-700
[12]Yin H, Miao JF, Zhang YS. Protective effect of beta-casomorphin-7 on type 1 diabetes rats induced with streptozotocin[J]. Peptides.2010,31:1725-1729
[13]Han D-N, Zhang D-H, Wang L-P, et al. Protective effect of β-casomorphin-7 on cardiomyopathy of streptozotocin-induced diabetic rats via inhibition of hyperglycemia and oxidative stress[J]. Peptides.2013,44:120-126
[14]Boutet A, De Frutos CA, Maxwell PH, et al. Snail activation disrupts tissue homeostasis and induces fibrosis in the adult kidney[J]. EMBO J.2006,25:5603-5613
[15]Bhowmick NA, Ghiassi M, Bakin A, et al. Transforming growth factor-beta 1 mediates epithelial to mesenchymal transdifferentiation through a rhoa-dependent mechanism[J]. Mol. Biol. Cell.2001, 12:27-36
[16]Bienz M. Beta-catenin:A pivot between cell adhesion and wnt signalling[J]. Curr. Biol.2005, 15:R64-R67
[17]Kaimori A, Potter J, Kaimori J-y, et al. Transforming growth factor-beta 1 induces an epithelial-to-mesenchymal transition state in mouse hepatocytes in vitro[J]. J. Biol. Chem.2007, 282:22089-22101
[18]Burns WC, Twigg SM, Forbes JM, et al. Connective tissue growth factor plays an important role in advanced glycation end product-induced tubular epithelial-to-mesenchymal transition:Implications for diabetic renal disease[J]. J. Am. Soc. Nephrol.2006,17:2484-2494
[19]Yamagishi S, Matsui T. Advanced glycation end products, oxidative stress and diabetic nephropathy[J]. Oxidative Medicine and Cellular Longevity.2010,3:101-108
[20]Draper H, Hadley M. Malondialdehyde determination as index of lipid peroxidation[J]. Methods Enzymol.1990,186:421-431
[21]Gao Y, Zhang RR, Li JH, et al. Radix astragali lowers kidney oxidative stress in diabetic rats treated with insulin[J]. Endocrine.2012,42:592-598
[22]Wu D, Wen W, Qi C-L, et al. Ameliorative effect of berberine on renal damage in rats with diabetes induced by high-fat diet and streptozotocin[J]. Phytomedicine.2012,19:712-718
[23]Badid C, Desmouliere A, Babici D, et al. Interstitial expression of alpha-sma:An early marker of chronic renal allograft dysfunction[J]. Nephrol Dial Transpl.2002,17:1993-1998
[24]Zeisberg M, Kalluri R. The role of epithelial-to-mesenchymal transition in renal fibrosis[J]. J. Mol. Med-Jmm.2004,82:175-181
[25]Noh H, Oh EY, Seo JY, et al. Histone deacetylase-2 is a key regulator of diabetes- and transforming growth factor-beta 1-induced renal injury[J]. Am. J. Physiol-Renal.2009,297:F729-F739
[26]Zhang M, Liu M, Xiong M, et al. Schisandra chinensis fruit extract attenuates albuminuria and protects podocyte integrity in a mouse model of streptozotocin-induced diabetic nephropathy[J]. J. Ethnopharmacol.2012,141:111-118
[27]王予慧.氧化应激在糖尿病肾病鼠肾小管上皮细胞转分化中的作用及普罗布考干预研究[D]。中南大学硕士论文,2009
[28]Rhyu DY, Yang YQ, Ha HJ, et al. Role of reactive oxygen species in tgf-beta 1-induced mitogen-activated protein kinase activation and epithelial-mesenchymal transition in renal tubular epithelial cells[J]. J. Am. Soc. Nephrol.2005,16:667-675
[29]Gorowiec MR, Borthwick LA, Parker SM, et al. Free radical generation induces epithelial-to-mesenchymal transition in lung epithelium via a tgf-beta 1-dependent mechanism[J]. Free Radic. Biol. Med.2012,52:1024-1032
[1]Schena FP, Gesualdo L. Pathogenetic mechanisms of diabetic nephropathy[J]. J. Am. Soc. Nephrol. 2005,16:S30-S33
[2]Gurley SB, Coffman TM. The renin-angiotensin system and diabetic nephropathy[C]. Seminars in nephrology.2007;27:144-152
[3]Peach M. Renin-angiotensin system:Biochemistry and mechanisms of action[J]. Physiol. Rev. 1977,57:313-370
[4]Zatz R, Dunn BR, Meyer TW, et al. Prevention of diabetic glomerulopathy by pharmacological amelioration of glomerular capillary hypertension[J]. J. Clin. Invest.1986,77:1925
[5]Donoghue M, Hsieh F, Baronas E, et al. A novel angiotensin-converting enzyme-related carboxypeptidase (ace2) converts angiotensin i to angiotensin 1-9[J]. Circ. Res.2000,87:E1-E9
[6]Tom B, Dendorfer A, Jan Danser A. Bradykinin, angiotensin-(1-7), and ace inhibitors:How do they interact?[J]. Int J Biochem Cell B,2003,35:792-801
[7]Tikellis C, Johnston CI, Forbes JM, et al. Characterization of renal angiotensin-converting enzyme 2 in diabetic nephropathy[J]. Hypertension.2003,41:392-397
[8]王艳霞,张伟,韩东宁,等.血管紧张素转化酶2(Ace2)对大鼠肾氧化应激损伤的保护作用及其机制[J].农业生物技术学报.2011,19：881-886
[9]Turner AJ, Hooper NM. The angiotensin-converting enzyme gene family:Genomics and pharmacology[J]. Trends Pharmacol. Sci.2002,23:177-183
[10]Corvol P, Michaud A, Soubrier F, et al. Recent advances in knowledge of the structure and function of the angiotensin-i converting-enzyme[J]. J. Hypertens.1995,13:S3-S10
[11]Brown WV. Microvascular complications of diabetes mellitus:Renal protection accompanies cardiovascular protection[J]. Am J Cardiol.2008,102:10L-13L
[12]Colucci JA, Arita DY, Cunha TS, et al. Renin-angiotensin system may trigger kidney damage in nod mice[J]. J Renin-Angio-Aldo S.2011,12:15-22
[13]Hostetter TH, Troy J, Brenner B. Glomerular hemodynamics in experimental diabetes mellitus[J]. Kidney Int.1981,19:410-415
[14]Rossig L, Hermann C, Haendeler J, et al. Angiotensin ii-induced upregulation of map kinase phosphatase-3 mrna levels mediates endothelial cell apotosis[J]. Basic Res. Cardiol.2002,97:1-8
[15]Kobori H, Nangaku M, Navar LG, et al. The intrarenal renin-angiotensin system:From physiology to the pathobiology of hypertension and kidney disease[J]. Pharmacol. Rev.2007,59:251-287
[16]Mezzano SA, Ruiz-Ortega M, Egido J. Angiotensin ii and renal fibrosis[J]. Hypertension. 2001,38:635-638
[17]Yang JW, Dai CS, Liu YH. Hepatocyte growth factor gene therapy and angiotensin ii blockade synergistically attenuate renal interstitial fibrosis in mice [J]. J. Am. Soc. Nephrol.2002, 13:2464-2477
[18]Shiota A, Yamamoto K, Ohishi M, et al. Loss of ace2 accelerates time-dependent glomerular and tubulointerstitial damage in streptozotocin-induced diabetic mice [J]. Hypertens. Res.2010, 33:298-307
[19]Nadarajah R, Milagres R, Dilauro M, et al. Podocyte-specific overexpression of human angiotensin-converting enzyme 2 attenuates diabetic nephropathy in mice [J]. Kidney Int.2012, 82:292-303
[20]Wong DW, Oudit GY, Reich H, et al. Loss of angiotensin-converting enzyme-2 (ace2) accelerates diabetic kidney injury[J]. Am. J. Pathol.2007,171:438-451
[21]Qian Y-R, Guo Y, Wan H-Y, et al. Angiotensin-converting enzyme 2 attenuates the metastasis of non-small cell lung cancer through inhibition of epithelial-mesenchymal transition[J]. Oncol. Rep. 2013,29:2408-2414
[22]Oudit G, Herzenberg A, Chappell M, et al. Loss of angiotensin converting enzyme 2 (ace2) leads to the development of an age-dependent renal glomerular injury [J]. Circulation.2003,108:151-151
[23]Gwathmey TM, Pendergrass KD, Reid SD, et al. Angiotensin-(1-7)-angiotensin-converting enzyme 2 attenuates reactive oxygen species formation to angiotensin ii within the cell nucleus[J]. Hypertension.2010,55:166-171
[24]Zhong JC, Guo D, Chen CB, et al. Prevention of angiotensin ii-mediated renal oxidative stress, inflammation, and fibrosis by angiotensin-converting enzyme 2[J]. Hypertension.2011,57:314-322
[25]Ye MH, Wysocki J, Naaz P, et al. Differential expression of angiotensin converting enzyme (ace) and ace-related carboxypeptidase (ace2) in diabetic db/db mice [J]. Hypertension.2004, 43:1352-1352
[26]Ye M, Wysocki J, Naaz P, et al. Increased ace 2 and decreased ace protein in renal tubules from diabetic mice a renoprotective combination?[J]. Hypertension.2004,43:1120-1125
[27]Wysocki J, Soler MJ, Ye M, et al. Ace/ace2 expression in glomeruli from db/db mice with established nephropathy and the effect of chronic ace2 inhibition[J]. Nephrol Dial Transpl. 2007,22:268-268
[28]马畅.血管紧张素转化酶2(ACE2)在糖尿病大鼠肾损伤中的作用及其机制[D].南京农业大学硕士学位论文,2010。
[1]Paul M, Mehr AP, Kreutz R. Physiology of local renin-angiotensin systems[J]. Physiol. Rev. 2006,86:747-803
[2]Paravicini TM, Touyz RM. Redox signaling in hypertension[J]. Cardiovasc. Res.2006,71:247-258
[3]Shah SV, Baliga R, Rajapurkar M, et al. Oxidants in chronic kidney disease[J]. J. Am. Soc. Nephrol. 2007,18:16-28
[4]Wilson S. Role of oxygen-derived free radicals in acute angiotensin ⅱ--nduced hypertensive vascular disease in the rat[J]. Circ. Res.1990,66:722-734
[5]Peng ZZ, Hu GY, Shen H, et al. Fluorofenidone attenuates collagen i and transforming growth factor-beta l expression through a nicotinamide adenine dinucleotide phosphate oxidase-dependent way in nrk-52e cells[J]. Nephrology.2009,14:565-572
[6]Kawahara T, Ritsick D, Cheng G, et al. Point mutations in the proline-rich region of p22phox are dominant inhibitors of noxl-and nox2-dependent reactive oxygen generation [J]. J. Biol. Chem. 2005,280:31859-31869
[7]Okada H, Danoff TM, Kalluri R, et al. Early role of fspl in epithelial-mesenchymal transformation[J]. Am. J. Physiol-Renal.1997,273:F563-F574
[8]Yang JW, Liu YH. Dissection of key events in tubular epithelial to myofibroblast transition and its implications in renal interstitial fibrosis[J]. Am. J. Pathol.2001,159:1465-1475
[9]Yang JW, Dai CS, Liu YH. Hepatocyte growth factor gene therapy and angiotensin ii blockade synergistically attenuate renal interstitial fibrosis in mice[J]. J. Am. Soc. Nephrol.2002,13:2464-2477
[10]Burns WC, Velkoska E, Dean R, et al. Angiotensin ii mediates epithelial-to-mesenchymal transformation in tubular cells by ang 1-7/mas-l-dependent pathways[J]. Am. J. Physiol-Renal. 2010,299:F585-F593
[11]Chen JC, Chen JK, Harris RC. Angiotensin ii induces epithelial-to-mesenchymal transition in renal epithelial cells through reactive oxygen species/src/caveolin-mediated activation of an epidermal growth factor receptor-extracellular signal-regulated kinase signaling pathway[J]. Mol. Cell. Biol. 2012,32:981-991
[12]Zhou L, Xue H, Yuan P, et al. Angiotensin atl receptor activation mediates high glucose-induced epithelial-mesenchymal transition in renal proximal tubular cells[J]. Clin. Exp. Pharmacol. Physiol. 2010,37:e152-e157
[13]Mezzano SA, Ruiz-Ortega M, Egido J. Angiotensin ii and renal fibrosis[J]. Hypertension.2001, 38:635-638
[14]Jandeleit-Dahm K, Cooper ME. Hypertension and diabetes:Role of the renin-angiotensin system[J]. Endocrinol. Metab. Clin. North Am.2006,35:469-490
[15]Wang D, Chen Y, Chabrashvili T, et al. Role of oxidative stress in endothelial dysfunction and enhanced responses to angiotensin ii of afferent arterioles from rabbits infused with angiotensin ii[J]. J. Am. Soc. Nephrol.2003,14:2783-2789
[16]Zafari AM, Ushio-Fukai M, Akers M, et al. Role of nadh/nadph oxidase-derived h2o2 in angiotensin ii-induced vascular hypertrophy [J]. Hypertension.1998,32:488-495
[17]Sun L, Xiao L, Nie J, et al. P66shc mediates high-glucose and angiotensin ii-induced oxidative stress renal tubular injury via mitochondrial-dependent apoptotic pathway[J]. Am. J. Physiol-Renal. 2010,299:F1014-F1025
[18]Whittaker L, McArdle F, Jackson MJ, et al. Oxidative stress induced by hyperglycaemia and angiotensin ii in hk-2 cells[J]. Nephrol Dial Transpl.2005,20:V237-V237
[19]Chen L, LIU Be, ZHANG XI, et al. Influence of connective tissue growth factor antisense oligonucleotide on angiotensin ii-induced epithelial mesenchymal transition in hk2 cells1[J]. Acta Pharmacol Sin.2006,27:1029-1036
[20]Rodrigues-Diez R, Carvajal-Gonzalez G, Sanchez-Lopez E, et al. Pharmacological modulation of epithelial mesenchymal transition caused by angiotensin ii. Role of rock and mapk pathways[J]. Pharm. Res.2008,25:2447-2461
[21]Wolf G, Mueller E, Stahl R, et al. Angiotensin ii-induced hypertrophy of cultured murine proximal tubular cells is mediated by endogenous transforming growth factor-beta[J]. J. Clin. Invest.1993, 92:1366
[22]Song JH, Cha SH, Lee HJ, et al. Effect of low-dose dual blockade of renin-angiotensin system on urinary tgf-β in type 2 diabetic patients with advanced kidney disease[J]. Nephrol Dial Transpl. 2006,21:683-689
[23]Carvajal G, Rodriguez-Vita J, Rodrigues-Diez R, et al. Angiotensin ii activates the smad pathway during epithelial mesenchymal transdifferentiation[J]. Kidney Int.2008,74:585-595
[24]Chabrashvili T, Kitiyakara C, Blau J, et al. Effects of ang ii type 1 and 2 receptors on oxidative stress, renal nadph oxidase, and sod expression[J]. Am J Physiol-Reg I.2003,285:R117-R124
[25]Zimpelmann J, Kumar D, Levine DZ, et al. Early diabetes mellitus stimulates proximal tubule renin mrna expression in the rat[J]. Kidney Int.2000,58:2320-2330
[26]Mizuiri S, Hemmi H, Arita M, et al. Increased ace and decreased ace2 expression in kidneys from patients with iga nephropathy[J]. Nephron Clin Pract.2011,117:C57-C66
[27]Moon JY, Jeong KH, Lee SH, et al. Renal ace and ace2 expression in early diabetic rats[J]. Nephron Exp Nephrol.2008,110:E8-E16
[28]Gwathmey TM, Pendergrass KD, Reid SD, et al. Evidence that the ace2-angiotensin-(1-7) pathway counterbalances angiotensin ii-induced formation of reactive oxygen species in renal nuclei[J]. Hypertension.2008,52:E124-E125
[29]Zhong J, Oudit GY, Basu R, et al. Recombinant human ace2 attenuates pressure overload-induced pathological myocardial remodeling[J]. Can. J. Cardiol.2010,26:71d-72d
[30]Qian Y-R, Guo Y, Wan H-Y, et al. Angiotensin-converting enzyme 2 attenuates the metastasis of non-small cell lung cancer through inhibition of epithelial-mesenchymal transition[J]. Oncol. Rep. 2013,29:2408-2414
[1]黄听,崔磊,曹谊林.STZ诱导裸鼠糖尿病模型的建立及观察[J].组织工程与重建外科杂志.2007,3：186-188
[2]Gunnarsson R, Berne C, Hellerstrom C. Cytotoxic effects of streptozotocin and n-nitrosomethylurea on the pancreatic b cells with special regard to the role of nicotinamide-adenine dinucleotide[J]. Biochem. J.1974,140:487-494
[3]Laue C, Kaiser A, Wendl K, et al. Reversal of streptozotocin-diabetes after transplantation of piscine principal islets to nude mice. Transpl P.2001;33:3504-3510
[4]Mukherjee B, Anbazhagan S, Roy A, et al. Novel implications of the potential role of selenium on antioxidant status in streptozotocin-induced diabetic mice[J]. Biomed. Pharmacother.1998,52: 89-95
[5]范英兰.β-酪啡肽-5对糖尿病大鼠血糖和氧化应激的影响[D].南京农业大学硕士学位论文,2010.
[6]印虹.β-酪啡肽7和酪蛋白水解肽对糖尿病大鼠血糖和氧化应激的影响[D].南京农业大学硕士学位论文,2010.
[7]韩东宁.β-酪啡肽-7对i型糖尿病大鼠心肌损伤的干预作用及其机制[D].南京农业大学硕士学位论文,2011.
[8]马畅.血管紧张素转化酶2(ace2)在糖尿病大鼠肾损伤中的作用及其机制[D].南京农业大学硕士学位论文,2010.
[9]Salpeter SR, Greyber E, Pasternak GA, et al. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus:Systematic review and meta-analysis[J]. Arch. Intern. Med.2003,163:2594
[10]宋晓丹.乳源β-酪啡肽-7降血糖作用及其机制的研究[D].南京农业大学硕士学位论文,2009.
[11]张源淑.酪啡肽的鉴定及其对仔猪消化道功能的影响研究[D].南京农业大学博士学位论文,2004.
[12]张必武,乐国伟,施用晖,等.乳蛋白源阿片肽-β-酪啡肽[J].饲料研究.2001,6：14-15
[13]宗亚峰.β酪啡肽在大鼠胃肠道内的释放、吸收和稳定特性及其对胃肠机能的影响[D].南京农业大学博士学位论文,2007.
[14]Yin H, Miao JF, Zhang YS. Protective effect of beta-casomorphin-7 on type 1 diabetes rats induced with streptozotocin[J]. Peptides.2010,31:1725-1729
[15]Han D-N, Zhang D-H, Wang L-P, et al. Protective effect of β-casomorphin-7 on cardiomyopathy of streptozotocin-induced diabetic rats via inhibition of hyperglycemia and oxidative stress[J]. Peptides.2013,44:120-126
[16]Schena FP, Gesualdo L. Pathogenetic mechanisms of diabetic nephropathy[J]. J. Am. Soc. Nephrol. 2005,16:S30-S33
[17]Yamagishi S, Matsui T. Advanced glycation end products, oxidative stress and diabetic nephropathy [J]. Oxid Med Cellular Longev.2010,3:101-108
[18]Ha H, Hwang I-A, Park JH, et al. Role of reactive oxygen species in the pathogenesis of diabetic nephropathy [J]. Diabetes Res. Clin. Pract.2008,82:S42-S45
[19]Draper H, Hadley M. Malondialdehyde determination as index of lipid peroxidation[J]. Methods Enzymol.1990,186:421-431
[20]Gao Y, Zhang RR, Li JH, et al. Radix astragali lowers kidney oxidative stress in diabetic rats treated with insulin[J]. Endocrine.2012,42:592-598
[21]Wu D, Wen W, Qi C-L, et al. Ameliorative effect of berberine on renal damage in rats with diabetes induced by high-fat diet and streptozotocin[J]. Phytomedicine.2012,19:712-718
[22]Nath KA. The tubulointerstitium in progressive renal disease[J]. Kidney Int.1998,54:992-994
[23]Badid C, Desmouliere A, Babici D, et al. Interstitial expression of alpha-sma:An early marker of chronic renal allograft dysfunction[J]. Nephrol Dial Transpl.2002,17:1993-1998
[24]Kalluri R, Neilson EG. Epithelial-mesenchymal transition and its implications for fibrosis[J]. J. Clin. Invest.2003,112:1776-1784
[25]Noh H, Oh EY, Seo JY, et al. Histone deacetylase-2 is a key regulator of diabetes-and transforming growth factor-beta 1-induced renal injury[J]. Am. J. Physiol-Renal.2009,297:F729-F739
[26]Zhang M, Liu M, Xiong M, et al. Schisandra chinensis fruit extract attenuates albuminuria and protects podocyte integrity in a mouse model of streptozotocin-induced diabetic nephropathy [J]. J. Ethnopharmacol.2012,141:111-118
[27]Corvol P, Michaud A, Soubrier F, et al. Recent advances in knowledge of the structure and function of the angiotensin-i converting-enzyme [J]. J. Hypertens.1995,13:S3-S10
[28]Zimpelmann J, Kumar D, Levine DZ, et al. Early diabetes mellitus stimulates proximal tubule renin mrna expression in the rat[J]. Kidney Int.2000,58:2320-2330
[29]Ye MH, Wysocki J, Naaz P, et al. Differential expression of angiotensin converting enzyme (ace) and ace-related carboxypeptidase (ace2) in diabetic db/db mice[J]. Hypertension.2004,43:1352-1352
[30]Ye M, Wysocki J, Naaz P, et al. Increased ace 2 and decreased ace protein in renal tubules from diabetic mice a renoprotective combination?[J]. Hypertension.2004,43:1120-1125
[31]Paravicini TM, Touyz RM. Redox signaling in hypertension[J]. Cardiovasc. Res.2006,71:247-258
[32]Shah SV, Baliga R, Rajapurkar M, et al. Oxidants in chronic kidney disease[J]. J. Am. Soc. Nephrol. 2007,18:16-28
[33]Zafari AM, Ushio-Fukai M, Akers M, et al. Role of nadh/nadph oxidase-derived h2o2 in angiotensin ii-induced vascular hypertrophy [J]. Hypertension.1998,32:488-495
[34]Loot AE, Schreiber JG, Fisslthaler B, et al. Angiotensin ii impairs endothelial function via tyrosine phosphorylation of the endothelial nitric oxide synthase[J]. J Exp Med.2009,206:2889-2896
[35]Pueyo ME, Gonzalez W, Nicoletti A, et al. Angiotensin ii stimulates endothelial vascular cell adhesion molecule-1 via nuclear factor-κb activation induced by intracellular oxidative stress[J]. Arterioscler. Thromb. Vasc. Biol.2000,20:645-651
[36]An SJ, Boyd R, Zhu M, et al. Nadph oxidase mediates angiotensin ii-induced endothelin-1 expression in vascular adventitial fibroblasts[J]. Cardiovasc. Res.2007,75:702-709
[37]Kawahara T, Ritsick D, Cheng G, et al. Point mutations in the proline-rich region of p22phox are dominant inhibitors of noxl-and nox2-dependent reactive oxygen generation[J]. J. Biol. Chem. 2005,280:31859-31869
[38]Oudit GY, Herzenberg AM, Kassiri Z, et al. Loss of angiotensin-converting enzyme-2 leads to the late development of angiotensin ii-dependent glomerulosclerosis[J]. Am J Pathol.2006,168:1808-1820
[39]Gwathmey TM, Pendergrass KD, Reid SD, et al. Angiotensin-(1-7)-angiotensin-converting enzyme 2 attenuates reactive oxygen species formation to angiotensin ii within the cell nucleus[J]. Hypertension.2010,55:166-171
[40]Zhong J, Guo D, Chen CB, et al. Prevention of angiotensin ii-mediated renal oxidative stress, inflammation, and fibrosis by angiotensin-converting enzyme 2[J]. Hypertension.2011,57:314-322
[41]Yang JW, Dai CS, Liu YH. Hepatocyte growth factor gene therapy and angiotensin Ⅱ blockade synergistically attenuate renal interstitial fibrosis in mice[J]. J. Am. Soc. Nephrol. 2002,13:2464-2477