The Role of TGF-β1/SMAD in Diabetic Nephropathy: Mechanisms and Research Development

Abstract

<p>Diabetic nephropathy (DN) is a common complication of diabetes and a leading cause of end-stage renal disease. Transforming growth factor-β1 (TGF-β1)/SMAD signaling activation plays an important role in the onset and progression of DN. Reported findings suggest that the activation of TGF-β1 (including the latent form, the active form, and the receptors) and its downstream signaling proteins (SMAD3, SMAD7, etc.) plays a critical role in DN. In addition, TGF-β1/SMAD signaling may mediate the pathogenesis and progression of DN via various microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). Emerging evidence shows that TGF-β1, SMAD3, and SMAD7 are the main signaling proteins that contribute to the development of DN, and that they can be potential targets for the treatment of DN. However, recent clinical trials have shown that the anti-TGF-β1 monoclonal antibody treatment fails to effectively alleviate DN, which suggests that upstream inhibition of TGF-β1/SMAD signaling does not alleviate clinical symptoms and that this may be related to the fact that TGF-β1/SMAD has multiple biological effects. Targeted inhibition of the downstream TGF-β1 signaling (e.g., SMAD3 and SMAD7) may be an effective approach to attenuate DN. This article discussed the current understanding of the molecular mechanisms and potential targets for the treatment and prevention of DN by focusing on TGF-β1/SMAD signaling.<br></p>

糖尿病肾病是糖尿病常见的并发症，也是导致终末期肾病的重要原因之一。转化生长因子-β1（transforming growth factor-β1, TGF-β1）/SMAD信号活化是糖尿病肾病发病及进展的主要机制之一。研究表明，TGF-β1（前体、本体、受体）及其下游信号蛋白（SMAD3、SMAD7等）的活化，在糖尿病肾脏损伤中起了关键的作用。此外，TGF-β1/SMAD可通过多种miRNA和lncRNA等介导糖尿病肾病的发病及进展。TGF-β1、SMAD3和SMAD7作为糖尿病肾脏损伤的主要蛋白，成为防治糖尿病肾病的关键靶点。近期临床试验显示TGF-β1单克隆抗体治疗无法有效减缓糖尿病肾病。提示在TGF-β1/SMAD信号上游抑制TGF-β1/SMAD并无减轻临床症状的作用，可能与其具有多种生物效应有关。靶向抑制TGF-β1下游信号分子（如SMAD3、SMAD7）可能是减轻糖尿病肾脏损伤的有效方法。本文总结了与TGF-β1/SMAD相关的糖尿病肾病发病机制，并讨论抗TGF-β1/SMAD信号防治糖尿病肾病的可能靶点。