足细胞脂质蓄积与足细胞损伤及慢性肾脏病（CKD）进展密切相关，但导致足细胞脂质蓄积的机制仍不清楚。肾素血管紧张素系统激活这一CKD进展的主要危险因素是否影响足细胞脂代谢也未见报道。SIRT6是细胞胆固醇代谢的重要调节分子，我们前期研究发现血管紧张素Ⅱ（AngⅡ）可抑制足细胞SIRT6表达和诱导足细胞胆固醇蓄积。本项目拟研究SIRT6在AngⅡ诱导足细胞胆固醇蓄积与损伤中的作用及机制。通过对AngⅡ输注动物模型、培养足细胞及足细胞病患者肾活检标本的研究，评价SIRT6表达与足细胞胆固醇蓄积和损伤的关系；通过SIRT6质粒转染、CRISPR/Cas9技术构建SIRT6敲除足细胞株以及应用特异性足细胞SIRT6基因敲除小鼠，探讨调控SIRT6表达对足细胞胆固醇蓄积与足细胞损伤的影响；通过药物调节细胞内胆固醇代谢，明确胆固醇蓄积对足细胞损伤的影响及机制。本研究将为足细胞病治疗的新靶点提供理论依据。

Lipid accumulation in podocyte is closely related to podocyte injury and progression of chronic kidney disease (CKD), but the exact mechanism of the disregulated lipid metabolism remains unclear. Whether the renin angiotensin system (RAS) activation, a main risk factor for CKD progression, affects podocyte lipid metabolism is still unknown. SIRT6 plays an important role in regulation of cellular cholesterol. We have recently found that angiotensinⅡ(AngⅡ) can inhibit SIRT6 expression and induce lipid droplet generation in podocyte. This project intends to investigate the role and the potential mechanism of SIRT6 in regulation of podocyte cholesterol accumulation and podocyte injury. Firstly, we will evaluate the expression of SIRT6, cholesterol accumulation and podocyte injury in AngⅡ-infused animals, cultured human podocytes and renal biopsy specimens of patients with podocytopathies; Secondly, we will explore the mechanism of SIRT6 in regulation of podocyte cholesterol metabolism and podocyte injury via altering the expression of SIRT6 with its recombinant plasmid, stable SIRT6 knock out cell line by CRISPR/Cas9 technology and specific podocyte SIRT6 knockout mice; Finally, we will evaluate the effect of cholesterol accumulation on podocyte injury through changing cellular cholesterol content by specific inhibitors. This investigation will provide a theoretical evidence for a new therapeutic target of podocytopathy.