Transforming growth factor-beta1 and Smad4 signaling pathway down-regulates renal extracellular matrix degradation in diabetic rats.

Qin Yang, Ru-jia Xie, Ting Yang, Li Fang, Bing Han, Guo-zhong Zhang, Ming-liang Cheng
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Abstract

Objective: To investigate the role of transforming growth factor-beta1 (TGF-beta1)/Smad4 pathway in development of renal fibrosis in streptozotocin (STZ)-induced diabetic nephropathy (DN) rats and explore its possible mechanism.

Methods: Male Wistar rats weighing 180-220 g were divided into 5 groups: group A (normal control), group B [diabetes mellitus (DM) 2 weeks], group C (DM 4 weeks), group D (DM 8 weeks), and group E (DM 16 weeks). Except for the normal control group, other groups were induced DM by single injection of STZ (55 mg/kg) respectively. Blood glucose level, serum creatinine, and 24-hour urine protein were examined. Expressions of TGF-beta1 and Smad4 protein and mRNA in kidney were detected using immunohistochemical technique, Western blot, and real-time PCR. mRNA expressions of stromelysin-1 (MMP-3), tissue inhibitor of metalloproteinase-1 (TIMP-1), and collagen In in kidney were also detected by real-time PCR.

Results: The levels of blood glucose, serum creatinine, and 24-hour urine protein in rats of group B, C, D, and E were higher than those of the control group. With the progression of renal fibrosis, the expressions of TGF-beta1 and Smad4 protein and mRNA in kidney of diabetic rats elevated. In addition, the renal MMP-3 mRNA expression diminished in diabetic rats, while TIMP-1 and collagen III mRNA increased.

Conclusions: In STZ-induced diabetic rats, the TGF-beta1/Smad4 appears to play an important role in renal fibrosis of DN. The increased expression of TGF-beta1 and Smad4 might result in the transcriptional regulation of downstream target genes of TGF-beta1/Smad4 pathway, which contributes to the progression of renal fibrosis in diabetic rats.

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转化生长因子- β 1和Smad4信号通路下调糖尿病大鼠肾细胞外基质降解。
目的:探讨转化生长因子- β 1 (tgf - β 1)/Smad4通路在链脲佐菌素(STZ)诱导的糖尿病肾病(DN)大鼠肾纤维化中的作用并探讨其可能机制。方法:体重180 ~ 220 g的雄性Wistar大鼠分为5组:A组(正常对照)、B组(糖尿病2周)、C组(糖尿病4周)、D组(糖尿病8周)、E组(糖尿病16周)。除正常对照组外,其余各组均采用STZ单次注射(55 mg/kg)诱导DM。检测血糖、血清肌酐、24小时尿蛋白。采用免疫组织化学、Western blot、real-time PCR检测肾组织tgf - β 1、Smad4蛋白及mRNA的表达。real-time PCR检测肾组织基质溶素-1 (MMP-3)、金属蛋白酶-1组织抑制剂(TIMP-1)和胶原蛋白In的mRNA表达。结果:B、C、D、E组大鼠血糖、血清肌酐、24小时尿蛋白水平均高于对照组。随着肾脏纤维化的进展,糖尿病大鼠肾脏中tgf - β 1和Smad4蛋白及mRNA的表达升高。此外,糖尿病大鼠肾脏MMP-3 mRNA表达降低,TIMP-1和胶原III mRNA表达升高。结论:在stz诱导的糖尿病大鼠中,tgf - β 1/Smad4在DN肾纤维化中起重要作用。TGF-beta1和Smad4的表达增加可能导致TGF-beta1/Smad4通路下游靶基因的转录调控,参与糖尿病大鼠肾纤维化的进展。
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