清道夫受体（SR）A可介导细胞摄取脂质，由于不受细胞内胆固醇的负反馈调节，在脂质肾脏损伤中起关键作用，但机制不明。我们新近研究发现：敲除PTEN可促进高脂饮食小鼠肾小球硬化和YAP的活化，在体外上调核转录因子YAP可使ox-LDL刺激的足细胞SR-A表达增加，我们推测PTEN/YAP通过上调足细胞SR-A表达参与脂质肾脏损伤。本研究拟①进一步观察高脂饮食对小鼠肾脏组织中PTEN、YAP活性和SR-A表达的影响；②明确调控PTEN表达对ox-LDL刺激的足细胞YAP活化、调控YPA对SR-A表达的影响，阐明PTEN确切的靶蛋白及精确作用位点；③制作足细胞特异性条件表达PTEN的小鼠模型，证实PTEN在高脂饮食小鼠中潜在的肾脏保护作用。本项目以探讨SR-A反馈调节新机制为切入点，深入揭示PTEN/YAP信号通路在高脂诱导的肾小球硬化中的作用，有可能在SR-A的上游获得干预脂质肾脏损伤的新靶标。

Dyslipidemia promotes progression of chronic kidney disease (CKD) by causing inflammatory, oxidative and ER stress. Our previous study found that scavenger recepor A (SR-A), which was up-regulated by the increased level of cytolipids, accelerated progressive nephropathy in high fat diet (HDF) mice by increasing the lipid-uptaking and inflammation. However, the exact mechanism of this postive feedback ragulation remains unclear. Recently, our preliminary data suggested that partailly deletion of PTEN markedly deteriorated the glomerulosclerosis by increaseing the podocyte apoptosis in lipid-induced nephropathy mice model. And this processe was attributed to the activation of Hippo-YAP pathway. Based on our novel observations and the several line of studies, which reported that YAP signaling pathway has emerged as a major regulator of cell proliferation and survival in metazoans, we argue that PTEN/YAP plays a critical role in the progressive nephropathy induced by HFD via its involvement in the up-regulation of SR-A. We now propose an integrated in vitro and in vivo approach to test the hypothesis that the inhibiting PTEN will increase SR-A expression in ox-LDL treated podocytes, and to identify the specific conponent and the specific phosporylation site which PTEN combined with. In vivo, with the new constructed podocyte specific PTEN knockin mice model, we will observer the effect of overexpression of PTEN in podocytes on the lipid-induced glomerulosclerosis. 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 PTEN/YAP pathway. It will lead to development of novel therapeutic strategies in the prevention of progression of CKD.