醛固酮通过抑制Nedd4L促进细胞焦亡在糖尿病肾小管-间质纤维化中的作用研究

糖尿病肾病(DKD)发病机制复杂且疗效不佳。临床研究表明，DKD患者血清醛固酮(Aldo)增高与蛋白尿、肾功能降低密切相关，但机制未阐明。Aldo通过MR上调靶基因SGK1，进而抑制Nedd4L介导的ENaC泛素化降解，是促进钠水重吸收的机制。我们发现高糖导致Nedd4L减少，使Caspase-5/11泛素化减少而表达和活化增加，促进了肾小管上皮细胞(RTECs)焦亡，给予Aldo可进一步加重该现象。因此，我们推测高糖可通过Aldo-MR上调SGK1，进而抑制Nedd4L泛素化Caspase-4/5/11，激活的Caspase-4/5/11剪切GSDMD促进RTECs焦亡，导致肾小管-间质纤维化(TIF)。本项目拟从DKD患者、糖尿病小鼠、RTECs多个层面，通过临床资料、动物模型、分子生物学实验，阐明高糖环境中Aldo抑制Nedd4L促进RTECs焦亡在糖尿病TIF中的作用和机制。

The pathogenesis of diabetic kidney disease (DKD) is complicated and the curative effect is not good. The increase of serum aldosterone (Aldo) in patients with DKD is closely related to urinary protein and reduced renal function, but the mechanism has not been elucidated. Aldo up-regulates the target gene SGK1 through MR to inhibit the ubiquitin degradation of ENaC mediated by Nedd4L, which is the mechanism of facilitating water and sodium reabsorption.We found that the decrease of Nedd4L induced by high glucose resulted out the decrease of ubiquitin and the increase of expression and activation of Caspase-5/11, promoted pryptosis in renal tubular epithelial cells(RTECs), which was further aggravated by aldosterone. We speculate that high glucose may up-regulate SGK1 to inhibit Nedd4L to ubiquitinate Caspase-4/5/11 protein via Aldo-MR pathway, and activate 4/5/11 to cleave GSDMD which enhance RTECs pyroptosis, resulting in tubulointerstitial fibrosis. We intend to DKD patients,Kidney tissues of mice with diabetes mellitus(DM) and renal tubular epithelial cells under high-glucose cultivation as the research objects, we intend to apply clinical data, animal models and molecular biology experiments to uncover the role and mechanism of Aldo suppressing Nedd4L to promote RTECs pyroptosis in tubulointerstitial fibrosis during diabetic kidney disease .