线粒体分裂与融合失衡是糖尿病肾脏病足细胞损伤的关键环节，但具体机制未明。我们预实验显示：高糖引起足细胞线粒体过度分裂，激活COX2-血栓素轴，抑制COX2可改善高糖诱导足细胞损伤及血栓素A2合成；进一步研究发现，下调血栓素受体可减轻高糖诱导线粒体功过度分裂，抑制ROCK1的表达及活性。据此，我们假设：高糖激活足细胞COX2-血栓素轴，活化RhoA-ROCK1通路，导致线粒体过度分裂，诱导足细胞损伤，启动并促进糖尿病肾脏病的发生和发展。为此，我们拟采用血栓素受体敲除的糖尿病小鼠，体外培养人足细胞，检测足细胞和线粒体功能的改变，从体内和体外两方面明确COX2-血栓素轴在糖尿病肾脏病足细胞线粒体功分裂与融合失衡中的关键作用及RhoA-ROCK1通路在其中的作用。该课题将揭示COX2-血栓素轴在糖尿病肾脏病足细胞线粒体分裂与融合失衡的关键作用和机制，为糖尿病肾脏病的防治提供潜在治疗靶点。

Imbalance of fission and fusion in mitochondrial are the key steps in the damage of podocyte in diabetic kidney disease, but the exact mechanism remains unknown. Our poilt experiments indicated: high glucose could lead to mitochondrial over-fission and stimulate COX2-thromboxane expression in podocytes, and the inhibition of COX2 could improve high-glucose-induced podocyte injury and reduce thromboxane A2 synthesis; down-regulation of thromboxane receptor by SiRNA could attenuate mitochondrial dysfunction and fragmentation, reduce ROCK1 expression and activity induced by high glucose. Accordingly, we hypothesize that high glucose stimulates the COX2-thromboxane pathway of podocytes, then activates the RhoA-ROCK1 pathway, leading to over spilting of mitochondria, inducing podocyte injury, initiating and promoting the development and progression of diabetic kidney disease. To this end, we developed type 1 and type 2 thromboxanereceptor knockout diabetic mice, cultured human podocytes in vitro, measured podocyte and mitochondrial function changes, to clarify the key role of COX2-thromboxane axis in the regulation of imbalance of podocyte mitochondrial fission and fusion, and the role of RhoA-ROCK1 pathway in the regulation. The study will clarify the key role and new mechanism of imbalance in the regulation of of podocyte mitochondrial fission and fusion in diabetic kidney disease, help to form a potential therapeutic target in the prevention and treatment of diabetic kidney disease.