我国约有10%成年人患有糖尿病，糖尿病肾病是糖尿病常见的微血管并发症，是导致终末期肾病的主要原因；然而，迄今尚无有效的治疗方法及治疗药物。近期研究发现内皮细胞损伤是糖尿病肾病重要的始动因素，且线粒体自噬受损参与其中，但确切机制尚不清楚。我们的前期工作表明选择性地抑制转录因子FoxO1可以减少线粒体分裂，诱导自噬，并显著改善糖尿病小鼠肾功能；同时FoxO1可能通过线粒体自噬的调控分子Mfn2和mTORC1调节线粒体功能。据此我们提出假设：糖尿病时，内皮细胞中FoxO1的持续活化通过激活下游信号通路mTORC1-Mfn2，引发线粒体自噬受损，线粒体功能障碍，肾功能损伤。本申请将1）明确内皮细胞中FoxO1调控线粒体自噬的确切分子机制，2）阐明其在糖尿病肾病中的作用。本研究将为揭示糖尿病肾病的分子机制，以及寻找糖尿病血管并发症的治疗药物提供重要的科学依据。

The prevalence of diabetes is about 10% in China. Diabetic kidney disease (DKD) is a common microvascular complication in diabetes, the main cause of end stage renal disease with limited treatment regimens. Recent studies have shown that endothelial abnormalities emerge as a key player in DKD, and impaired mitophagy involved, but the underlying mechanisms are poorly understood. Our preliminary data indicates that selective inhibition of transcription factor FoxO1 chould suppress mitochondrial fission, induce autophagy, and significantly improve the renal function of diabetic mice. In addition, FoxO1 may be involved in regulation of Mfn2 and mTORC1 which are required for mitophagy. So we hypothesized that FoxO1 may induce diminished mitophagy by activation of mTORC1-Mfn2 in endothelial cells, which leads to impaired renal function in diabetes. This project will focus on 1) identify the mechanism whereby FoxO1 regulates mitophagy in endothelial cells, 2) determine its role in DKD. The proposed studies will provide new knowledge regarding mechanisms of DKD, thus addressing a fundamental issue for new approaches in treatment and prevention of diabetic vascular disease.