AIM: To investigate the effect of epidermal growth factor receptor (EGFR) inhibitor erlotinib on kidney injury in diabetic nephropathy (DN) rat and the underlying mechanism.METHODS: The rat model of DN was induced by intraperitoneal injection of streptozotocin (STZ) at dose of 55 mg/kg.One week after STZ injection, the rats with blood glucose level exceeding 16.7 mmol/L were identified as diabetic.Diabetic rats were randomly divided into 2 groups: STZ group and STZ+erlotinib group.In addition, the normal rats were used as control group.The rats in STZ+erlotinib group were treated with erlotinib at 100 mg·kg-1·d-1 for 4 weeks(5th~8th week).The fasting blood glucose (FBG), serum creatinine (SCr) and 24 h urine protein were measured.The pathological changes of the kidney were observed by HE staining and Masson staining.The protein levels of EGFR, p-EGFR, transforming growth factor β1 (TGFβ1), Smad2/3, p-Smad2/3, collagen Ⅳ (ColⅣ) and fibronectin in the kidney tissues were determined by Western blot.The reactive oxygen species (ROS) level and malondialdehyde (MDA) content in the renal tissues were futher analyzed.RESULTS: Compared with control group, the levels of FBG, 24 h urine protein and Scr were significantly increased in STZ group (P<0.01).Compared with STZ group, the levels of FBG, 24 h urine protein and SCr in STZ+erlotinib group were markedly decreased (P<0.05).In additon, the glomerular structure was restored to normal, the proliferative degree of mesangial cells markedly attenuated, and the epithelial cells were in alignment in STZ+erlotinib group.Moreover, erlotinib significantly inhibited the protein levels of p-EGFR, TGFβ1, p-Smad2/3, ColⅣ and fibronectin in the kidney tissues of STZ rats.In addition, erlotinib also significantly inhibited the levels of ROS and MDA in the kidney tissues of STZ rats.CONCLUSION: Erlotinib ameliorates STZ-induced diabetic nephropathy possibly through inhibiting the activation of EGFR/TGFβ1-Smad2/3 signaling pathway in association with suppression of fibrosis and oxidative stress.%目的: 研究表皮生长因子受体(EGFR)抑制剂厄洛替尼(erlotinib)对糖尿病肾病大鼠肾脏的保护作用及机制.方法: 采用大剂量(55 mg/kg)链脲佐菌素(STZ)腹腔注射诱导大鼠糖尿病肾病模型,以1周后血糖值>16.7 mmol/L的大鼠为造模成功的标准.将糖尿病大鼠随机分为2组[STZ组和STZ+erlotinib(100 mg·kg-1·d-1)组],并以正常大鼠为对照组 (control 组).Erlotinib处理4周后,检测大鼠空腹血糖、血清肌酐和24 h尿蛋白含量的变化;HE染色和Masson染色观察肾脏组织病理学改变;Western blot检测各组肾脏组织中EGFR、p-EGFR、转化生长因子β1(TGFβ1)、Smad2/3、p-Smad2/3、Ⅳ型胶原蛋白(ColⅣ)和纤连蛋白(fibronectin)的蛋白水平;活性氧簇(ROS)和丙二醛(MDA)试剂盒分别检测各组肾脏组织中ROS和MDA水平.结果: 与control组相比,STZ组血糖、24 h尿蛋白和血清肌酐水平均显著升高(P<0.01),肾组织形态学出现异常变化;与STZ组相比,STZ+erlotinib组的血糖、24 h尿蛋白水平和血清肌酐水平显著降低(P<0.05),肾小球结构恢复正常,肾小球系膜细胞增生程度明显减弱.厄洛替尼明显抑制了STZ大鼠肾组织中p-EGFR、TGFβ1、p-Smad2/3、ColⅣ和fibronectin蛋白水平,也明显抑制了STZ大鼠肾组织中ROS和MDA水平.结论: 厄洛替尼可能通过抑制EGFR/TGFβ1-Smad2/3信号通路的激活来抑制糖尿病肾病肾组织的纤维化和氧化应激反应,从而减轻肾损伤.
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