ATP-P2X4信号轴介导的线粒体自噬不足在糖尿病肾病中的作用和机制

肾小管上皮细胞线粒体损伤是糖尿病肾病（DN）肾间质炎症和细胞凋亡的关键原因。自噬是细胞清除受损线粒体的重要机制。然而DN时肾小管上皮细胞线粒体自噬不足，具体机制不清。现已经证明ATP-P2X4信号轴在DN肾脏炎症和细胞凋亡中起着重要作用。我们前期发现阻断ATP-P2X4信号轴能够抑制高糖负荷下TXNIP的表达，进而通过上调PINK1活性增强线粒体自噬。据此我们首次提出ATP-P2X4信号轴介导线粒体自噬不足的可能性。本项目拟通过体内实验明确P2X4在DN线粒体自噬、炎症反应及细胞凋亡等病理生理过程中的调控作用。并在体外实验解析ATP-P2X4信号轴在线粒体自噬不足的作用环节及分子机制。本项目从线粒体自噬的全新视角解析DN的发病机制，进而为DN的防治提供新的靶点和理论依据。

Mitochondrial damage of tubular epithelial cell is a key cause of renal interstitial inflammation and cell apoptosis in diabetic nephropathy (DN). Autophagy is an important way to eliminate damaged mitochondria. However, mitochondrial autophagy is insufficient in renal tubular epithelial cells in DN. And the mechanism of mitochondrial autophagy insufficiency is unclear. It is demonstrated ATP-P2X4 signaling axis plays an important role in renal inflammation and cell apoptosis in DN. Our previous study found that blocking ATP-P2X4 signaling axis could inhibit the expression of TXNIP under high glucose and enhance mitochondrial autophagy activity by upregulating PINK1. Accordingly, we first proposed ATP-P2X4 signal axis may mediate mitochondrial autophagy insufficiency in diabetic nephropathy. We plan to confirm the role of P2X4 in mitochondrial autophagy, inflammation and apoptosis in vivo. On the other hand, we investigate the role of ATP-P2X4 signaling axis in mitochondrial autophagy insufficiency and its molecular mechanism in vitro. In this project we study the pathogenesis of DN from a new perspective of mitochondrial autophagy, and provide a new theory and possible targets for prevention and treatment of DN.