自噬对脂肪酸β氧化的调控效应在糖尿病肾血管内皮细胞脂毒性中的作用

Vascular endothelial cells dysfunction plays a key role in the pathogenesis of diabetic nephropathy, while the precise mechanism is not fully understood. Related studies, along with our previous studies, have demonstrated that lipotoxicity might be the common pathogenic mechanism underlying diabetes-induced multiple renal resident cell injury, including mesangial cell, podocytes and tubular epithelial cells. However, the role of lipotoxicity in diabetes-related endothelial cells dysfunction is unclear. Furthermore, recent studies suggested that autophagy might be a novel regulating mechanism of intracellular lipid metabolism. Disturbed autophagy has been evidenced as an important upstream mechanism responsible for elevated cellular lipid deposition in several lipotoxic diseases. Our previous studies also suggested that altered autophagy might be involved in the pathogenesis of lipotoxicity in tubular epithelial cells. Whether disturbed autophagy also participates in endothelial cells lipotoxicity needs further investigation. The present study aims to explore the role of lipotoxicity in diabetes-induced glomerular endothelial cells injury and whether altered autophagy might act as an upstream mechanism underlying glomerular endothelial cells lipotoxicity. The present study might help to better the current knowledge of the pathogenesis of diabetic nephropathy, and explore novel intervening methods as well.

肾血管内皮细胞损伤是糖尿病肾病发生发展的重要环节，但具体机制尚未完全阐明。国内外相关研究以及项目组的前期研究均证实，脂毒性是糖尿病状态下肾小球系膜细胞、足细胞以及肾小管上皮细胞损伤的共同致病机制。脂毒性在糖尿病肾血管内皮细胞损伤的地位和作用目前尚不清楚。新近研究发现，自噬参与细胞脂代谢调节。自噬异常可导致细胞内脂代谢紊乱，与多种脂毒性疾病的发生有关。项目组前期研究也发现，自噬异常参与肾小管上皮细胞脂毒性的发生。自噬对脂代谢的调控作用是否同样参与肾血管内皮损伤发生目前尚不清楚。本项目以肾小球血管内皮细胞为观察对象，主要探讨以下两个主要问题：（1）脂毒性在糖尿病肾小球血管内皮细胞损伤中的地位和作用；（2）自噬对脂代谢的调控作用是否是肾小球血管内皮细胞脂毒性的一种上游机制。完成本项目对于深入理解糖尿病肾血管内皮细胞损伤的机制以及寻找可能的干预措施均具有重要意义。

本课题计划研究自噬对脂肪酸β氧化的调控效应在糖尿病肾血管内皮细胞脂毒性中的作用。在课题进展过程中课题发现自噬可改善高糖诱导的肾损伤，并且通过抑制胰岛素抵抗来发挥作用。同时高糖环境导致自噬适配器SQSTM1/p62在血管内皮细胞内广泛蓄积，进一步课题组探索发现SQSTM1／p62敲降可改善高糖状态下血管内皮细胞功能紊乱。脂毒性是糖尿病肾病发生发展的重要致病机制。自噬对于细胞内脂代谢具有调控作用，而自噬程序可由赖氨酸乙酰化控制。最后，课题组探索了乙酰化是如何参与肾脏脂毒性的发生和发展，发现线粒体特异性乙酰转移酶GCN5L1通过调控线粒体蛋白乙酰化参与调控脂肪酸代谢