肾小管上皮细胞损伤是糖尿病肾病（diabetic nephropathy,DN）的重要病理特征，与DN进展密切相关。最新研究提示线粒体自噬异常在高葡萄糖诱导肾小管上皮细胞损伤中起重要作用。我们前期研究发现：衔接蛋白P66Shc在调控高葡萄糖诱导的肾小管上皮细胞线粒体ROS生成及线粒体片段化中起重要作用，而细胞内线粒体ROS水平及线粒体片段化改变与线粒体自噬密切相关。但P66Shc介导肾小管上皮细胞线粒体自噬改变的具体调控机制及产生的病理效应尚未阐明。本项目采用细胞分子生物学技术，研究P66Shc-线粒体ROS、P66Shc-线粒体片段化对DN肾小管细胞线粒体自噬的调控作用与分子机制，并探讨线粒体自噬与DN肾小管细胞损伤的关系。确定P66Shc-线粒体ROS/线粒体片段化-线粒体自噬这一新通路在DN小管损伤中的关键作用，旨在阐明DN肾小管细胞损伤的新机制，并为延缓DN进展提供新的干预靶点。

It has been demonstrated that renal tubulointerstitial lesions is the early and original features of diabetic nephropathy(DN) and is significantly associated with the progression of DN. Mitophagy induced by high glucose has been recently proposed to play a critical role in the pathogenesis of tubulointerstitial injury in DN. We have shown earlier that P66Shc is a master regulator of renal tubular cell injury through mediating mitochondrial ROS production and mitochondrial fragmentation. In addition, excess mitochondrial ROS and mitochondrial fission may stimulate mitophagy activity in the kidney. Whereas under diabetic ambience，the precise role of P66Shc in mitophagy is still unclear, and the cytopathic effects of excessive mitophagy has also not been clarified yet. To explore these processes, in this project we will focus on verifing the effect of P66Shc- mitochondrial ROS and P66Shc- mitochondrial fragmentation on the regulation of mitophagy in tubular cells exposed to high glucose and confirming the role of mitophagy on tubular cell injury, as detection methods by cell molecular biology and STZ induced diabetic model rats. The aim of this subject is to unveil a new mechanism of tubular cell damage mediated by P66Shc, and provide a novel and effective target in fighting DN.