EZH2介导的自噬在脓毒症急性肾损伤中的作用机制研究

Endotoxemia in sepsis is a major cause of acute kidney injury (AKI) with high morbility and mortality. Unfortunately, there is no effective treatment apart from preventative measure. Autophagy is a conserved, cellular catabolic pathway that plays crucial roles in cellular homeostasis including the maintenance of cellular function and viability. Our previous study showed that autophagy was induced in kidney tubular cells in mice by the endotoxin lipopolysaccharide (LPS), and played a renoprotective role in kidney tubules. However, the underlying pathogenesis is poorly understood. Recently ,there are several studies indicate that EZH2, which is a histone lysine methylation transferase, playing an important role in kidney diseases such as diabetic nephropathy and renal fibrosis. In this study, we investigate the functional role of EZH2 in septic AKI with the proximal tubule knockout mice model and CAG-RFP-EGFP-LC3 autophage reporter mice model. We also use the EZH2 inhibitor GSK126 and cell model to explore the mechanism of EZH2 in septic AKI. Thus, we will provide theoretical and experimental basis for the treatment of septic AKI.

脓毒症是引起急性肾损伤（acute kidney injury, AKI）的重要原因之一，具有高致残率和致死率，目前除预防措施外，尚无有效治疗方案。自噬是指通过自噬体与溶酶体结合，在一系列水解酶的作用下完成对物质的再利用，从而维持机体的基本稳态。我们前期研究发现，自噬可以抑制细胞凋亡，在脓毒症相关AKI中起保护作用，但具体作用机制尚不清楚。最近研究提示，EZH2作为组蛋白赖氨酸甲基转移酶，可参与调控自噬，而且在多种肾脏疾病中发挥作用，如糖尿病肾病、肾脏纤维化等。本项目拟采用EZH2近端小管条件性敲除小鼠及CAG-RFP-EGFP-LC3自噬小鼠模型，观察EZH2对脓毒症相关AKI中自噬的调控作用，并通过EZH2特异性抑制剂GSK126及多种干扰RNA构建的细胞模型，探究可能的作用机制，以期为脓毒症肾损伤的治疗提供理论依据与实验基础。

脓毒症是引起急性肾损伤（acute kidney injury, AKI）的重要原因之一，具有高致残率和致死率，目前除预防措施外，尚无有效治疗方案。自噬是指通过自噬体与溶酶体结合，在一系列水解酶的作用下完成对物质的再利用，从而维持机体的基本稳态。我们前期研究发现，自噬可以抑制细胞凋亡，在脓毒症相关AKI中起保护作用，但具体作用机制尚不清楚。最近研究提示，EZH2作为组蛋白赖氨酸甲基转移酶，可参与调控自噬，而且在多种肾脏疾病中发挥作用，如糖尿病肾病、肾脏纤维化等。本项目拟采用EZH2近端小管条件性敲除小鼠及CAG-RFP-EGFP-LC3自噬小鼠模型，观察EZH2对脓毒症相关AKI中自噬的调控作用，并通过EZH2特异性抑制剂GSK126及多种干扰RNA构建的细胞模型，探究可能的作用机制，以期为脓毒症肾损伤的治疗提供理论依据与实验基础。