糖尿病肾病（DKD）是引起ESRD的主要病因，小管损伤和间质纤维化是其早期和原始特征，与本病进展密切相关。线粒体ROS增多，导致氧化损伤在DKD发病中起核心作用。最新发现，线粒体自噬是清除病变线粒体，降低ROS生成、调节细胞氧化损伤的关键。我们以往证明：DKD小管细胞线粒体形态和功能异常、ROS增加与小管凋亡相关。但线粒体自噬在其中的作用与调控机制尚不明。本项目采用细胞分子生物学技术与转基因动物，观察DKD小管细胞线粒体自噬与ROS的关系；研究PINK-Parkin、Nix/Bnip3、Atg7对DKD(高糖、Ang II)小管细胞线粒体自噬的影响；探讨线粒体自噬在DKD小管损伤和间质纤维化中的作用与分子机制；确立线粒体自噬-ROS-NLRP3这一新信号通路在DKD小管损伤及间质纤维化中的关键作用，旨在阐明DKD小管细胞线粒体介导的氧化损伤新机制，为DKD发病机制研究提供新思路与防治靶点。

Diabetic kidney disease (DKD) is the main cause of end stage renal disease (ESRD). It is suggested that tubular damage and interstitial fibrosis are the early and original features of ESRD and are closely associated to the progress of DKD. Increased Mitochondrial ROS can lead to cellular oxidative damage, which is very important to the pathogenesis of DKD. Mitophagy has been recently proposed to play a critical role in regulating intracellular oxidative damage through removal of the damaged mitochondria with decreasing ROS production. We found that mitochondria morphological change and dysfunction are contributed to ROS overproduction and apoptosis of tubule cells in DKD. However, whether mitophagy involved in this process and by which factor regulation of the mitophagy are still unknown. In this project we will focus on studing the relationship between mitophagy and ROS production under DKD condition, verify the effect of PINK-Parkin, Nix/Bnip3 and autophagy regulation protein Atg7 on the mitophagy of tubular cells exposed to high glucose and Angiotensin II，confirm the role of mitophagy on tubular damage and interstitial fibrosis, as detection methods by cell molecular biology and Agt7 condition knockout mouse. On the other hand, we also study the role of mitophagy-ROS-NLRP3 pathway in the tubular cell injury and fibrosis of DKD. The aim of the subject is to illustrate a new mechanism of tubular cell damage mediated by mitochondrial oxidative damage as well as provide a new theory in the pathogenesis and therapy targets of DKD.