DNA甲基化结合蛋白MeCP2抑制急性肾损伤的机制研究

Number of patients diagnosed with acute kidney injury (AKI) is fast increasing with a high mortality rate, and therapeutic drugs are lacking. Renal ischemia and reperfusion injury is a common cause of clinical diagnosed AKI, and the underlying mechanisms remain to be elucidated. In our pilot study, the applicant found that the level of DNA methylation-binding protein MeCP2 increased rapidly in the kidney after renal ischemia-reperfusion injury. The mechanistic study suggested that MeCP2 can directly bind to the DNA damage regulator PARP-1 through its NTD and MBD domains. After injury, renal tubular epithelial cell specific loss of MeCP2 mice showed a significant decrease in renal function and increased renal tissue damage, accompanied by increased inflammation and increased inflammatory cell infiltration, compared with the wildtype mice. Based on these pilot results, the applicant proposed a scientific working hypothesis that ‘MeCP2 inhibits acute kidney injury by regulating DNA damage pathway and inflammation/inflammatory cell infiltration’. In this proposal, we plan to use a variety of cellular and mouse models of gene knockout/overexpression to address following specific aims. ① Whether MeCP2 regulates acute kidney injury in renal tubular epithelial cells through DNA damage pathway and inflammation/inflammatory cell infiltration? ② Determination key domains of MeCP2 responsible for regulating acute renal injury, and the prospects of Mecp2 as a therapeutic target of acute kidney injury. This study aims to reveal the molecular mechanism of how MeCP2 affects AKI, and to provide a new angle for the prevention and treatment of the disease.

急性肾损伤（AKI）患者数量大、死亡率高、治疗药物缺乏。肾脏缺血损伤性损伤是引起AKI的普遍原因，其发生机制有待完善。申请人前期发现肾脏的DNA甲基化结合蛋白MeCP2水平在缺血再灌注损伤后急速升高，初步机制研究发现MeCP2通过其NTD及MBD结构域结合DNA损伤调控因子PARP-1；且损伤后，与野生型小鼠相比，肾小管上皮细胞特异性缺失MeCP2小鼠的肾功能显著下降、肾组织损伤加剧，伴随炎症上升及炎性细胞浸润增加。申请人据此提出“MeCP2通过调控DNA损伤通路及炎症和炎性细胞浸润来抑制肾脏急性损伤”科学假说。拟采用基因敲除/过表达的多种细胞和小鼠模型，研究①MeCP2在肾小管上皮细胞中通过DNA损伤通路及炎症和炎性细胞浸润调控急性肾损伤的分子机制；②确定MeCP2调控肾脏急性损伤的关键结构域及其作为治疗靶点的前景。本研究有望揭示MeCP2影响AKI的分子机制，为其防治提供新理论新方向。