JDRF Danielle Alberti Memorial Centre for Diabetes Complications, Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
Kidney Int. 2014 Feb;85(2):352-61. doi: 10.1038/ki.2013.372. Epub 2013 Oct 2.
Renal fibrosis results from excessive accumulation of extracellular matrix mainly driven by transforming growth factor-β1 (TGF-β1). Certain microRNAs have been implicated in this disease, and here we examine the role of let-7b. Rat proximal tubular epithelial cells (NRK52E) were treated with TGF-β1 for 3 days to assess the expression of markers of fibrosis and let-7b. These factors were also assessed in two mouse models representing early and more advanced diabetic nephropathy and in the non-diabetic adenine-induced renal fibrosis model. TGF-β1 downregulated the expression of let-7b and induced fibrogenesis in NRK52E cells. Ectopic expression of let-7b repressed TGF-β1 receptor 1 (TGFBR1) expression directly by targeting the two let-7b binding sites in the 3'-untranslated region of that gene, reduced expression of extracellular matrix proteins, decreased SMAD3 activity, and attenuated the profibrotic effects of TGF-β1. Knockdown of let-7b elevated TGFBR1 expression and mimicked some of the profibrotic effects of TGF-β1. Consistent with these observations, let-7b expression was also reduced in models of both diabetic and non-diabetic renal fibrosis with the upregulation of TGFBR1. Thus, let-7b microRNA represents a potential new target for the treatment of renal fibrosis in diabetic and non-diabetic nephropathy.
肾纤维化是由细胞外基质的过度积累引起的，主要由转化生长因子-β1（TGF-β1）驱动。某些 microRNAs 与这种疾病有关，我们在此研究了 let-7b 的作用。用 TGF-β1 处理大鼠近端肾小管上皮细胞（NRK52E）3 天，以评估纤维化和 let-7b 的标志物的表达。在两个代表早期和更晚期糖尿病肾病的小鼠模型以及非糖尿病腺嘌呤诱导的肾纤维化模型中也评估了这些因素。TGF-β1 下调了 let-7b 的表达，并在 NRK52E 细胞中诱导了纤维发生。let-7b 的异位表达通过靶向该基因 3'-非翻译区中的两个 let-7b 结合位点直接抑制 TGF-β1 受体 1（TGFBR1）的表达，降低细胞外基质蛋白的表达，降低 SMAD3 活性，并减弱 TGF-β1 的促纤维化作用。let-7b 的敲低增加了 TGFBR1 的表达，并模拟了 TGF-β1 的一些促纤维化作用。与这些观察结果一致，在糖尿病和非糖尿病肾纤维化模型中，let-7b 的表达也降低，同时 TGFBR1 上调。因此，let-7b microRNA 代表了治疗糖尿病和非糖尿病肾病肾纤维化的一个新的潜在靶点。
