我们在高脂饮食小鼠肾组织观察到：清道夫受体(SR)A可显著抑制自噬、促进脂质空泡形成，但SR-A参与自噬与脂质空泡变性的机制并不清楚。最近，我们在肾小管上皮(HK-2)细胞发现SR-A可介导脂质激活Rho激酶(ROCK),鉴于ROCK已被证实在自噬前体形成和溶酶体分布中具有重要作用，本课题拟在脂质刺激的HK-2细胞增强或抑制SR-A/ROCK信号，观察对自噬泡膜动力蛋白(MLC、Arp-2、CRMP-2)、自噬调节信号蛋白(PIK3/Akt)和自噬分子(Atg5、LC3-Ⅱ)的影响，探讨SR-A-ROCK信号通路与自噬特异性脂质降解的关系；在高脂饮食小鼠模型，进一步观察双重阻断SR-A/ROCK1对肾组织自噬特异性脂质降解、脂质空泡形成和肾脏纤维化的影响。本项目从SR-A-ROCK信号通路介导自噬特异性降解障碍的新视角探讨脂质肾脏损伤的机制，为延缓慢性肾脏病进展提供新思路。

Our previous study found that scavenger recepor A (SR-A) accelerated progressive nephropathy in high fat diet (HDF) mice by increasing the lipid vacuole formation and decreasing autophagy. However, the role and the mechanism of SR-A involved in the autophagy and the autophagy-specific lipid decomposition in the lipid-induced nephropathy remains unclear. Recently, our preliminary data suggested that SR-A modulated Rho kinase (ROCK) activity in oxidative low density lipoprotein (ox-LDL) treated human renal tubular epithelial cell (HK-2). Based on our those novel observations and the several line of studies, which reported that ROCK had been shown an important role in mediating various cellular processes, including cytoskeletal remodeling, membrane blebbing, and autophagy, we argue that SR-A plays a critical role in the progressive nephropathy induced by HFD via its involvement in ROCK-modulating autophagy and autophagy-specific lipid decomposition in present proposal. We now propose an integrated in vitro and in vivo approach to test two specific aims. Aim 1:To test the hypothesis that at the cellular level, SR-A-ROCK signal pathway modulateds the lipid vacuolar formation and the autophagy in lipid-stimulated HK-2 cells via regulating the phosphorylation of dynamic protein (MLC, Arp-2 CRMP-2) and autophagy signaling protein(PIK3/Akt), and the expression of autophgy molecules (Atg5、LC3-II、Beclin1). Aim 2: To test the hypothesis that dual deletion of SR-A/ROCK1 in the experimental model of lipid-induced kidney disease ameliorates the progression of nephropathy by inhibiting ROCK-mediated lipid vacuolar degeneration and increased autophagy-specific lipid decomposition.The successful completion of this proposal will provide a new insight into the pathogenesis of the lipid-induced nephropathy from a the stand point of SR-A-ROCK medicated autophagy dysfuntion. It will lead to development of novel therapeutic strategies in the prevention of progression of chronic kidney disease (CKD).