糖尿病肾病（DN）是糖尿病慢性微血管并发症，具有很高的致死致残率，然而其发病机制至今未明。近来研究发现，高糖诱发的细胞内短链脂肪酸代谢障碍在DN足细胞损伤中发挥关键作用。我们预实验结果证实，高糖作用下足细胞内乙酸含量显著增加，乙酰辅酶A合成酶2 (ACSS2)表达上调，足细胞Nephrin表达减少，α-SMA表达增加，然而高糖对Nephrin、α-SMA的作用能够被ACSS2抑制剂逆转。进一步研究发现，上述作用可能与沉默信息调节因子1(Sirt1)表达下调，介导雷帕霉素靶蛋白复合物1（mTORC1）通路活化密切相关，提示ACSS2通路激活可能介导了DN足细胞损伤的发生。因此，本研究拟通过制备DN及足细胞特异性ACSS2基因敲除小鼠模型、过表达Sirt1的足细胞培养模型，探讨高糖环境下ACSS2激活在调控Sirt1通路促进DN足细胞损伤中的作用及机制，从而为临床更新DN诊治策略提供实验依据。

Diabetic nephropathy (DN) is a chronic microvascular complication of diabetes mellitus with a high rate of mortality and disability. However, its mechanism has not been fully elucidated. Recent studies have found that intracellular metabolic disorders of short chain fatty acid induced by persistent high glucose play a key role in the development of podocyte damage in DN. Our preliminary results showed that podocytes produced excessive acetate under the stimulation of high glucose and then up-regulated the expression of acetyl coenzyme A synthase 2 (ACSS2), which resulted in the decrease of nephrin expression and the increase of alpha-SMA expression in podocytes. These effects were overrided by the use of ACSS2 inhibitors. Further studies found that these effects were closely associated with the down-regulation of silence information regulator 1 (Sirt1) expression mediated the activation of mammalian target of rapamycin protein complex 1 (mTORC1) pathway, suggesting that ACSS2 activation may mediate the podocyte injury in DN. Therefore, this study aims to explore the role of ACSS2 activation in podocyte injury and its potential mechanisms under the bachground of persistent high glucose by using DN mouse model, podocyte-specific ACSS2 knockout mouse model, and Sirt1-overexpressed podocyte cell culture model. This study is expected to to provide further experimental basis for the update of DN clinical diagnosis and treatment strategy.