mPGES-2在糖尿病肾病肾小管损伤及肾脏间质纤维化中的作用及机制研究

糖尿病肾病（DKD）是导致终末期肾病的主要病因，目前尚缺乏治疗DKD的特效药物。肾脏中，微粒体前列腺素E合酶2（mPGES-2）主要表达在肾小管细胞，对DKD的研究尚未见报道。我们前期研究发现db/db小鼠敲除mPGES-2显著改善肾小管损伤和肾脏纤维化，且明显降低肾脏丙二醛（MDA）的含量而非PGE2的水平。MDA是脂质过氧化的标志性产物，已有研究表明脂质过氧化产物可抑制p53的蛋白酶体降解，而MDA是否调控p53的蛋白稳定性尚不清楚。进一步研究发现db/db小鼠敲除mPGES-2明显降低p53的蛋白而不影响mRNA含量。故推测：mPGES-2可能通过合成MDA抑制p53的蛋白酶体降解参与DKD肾脏间质纤维化的发生和发展。本项目拟从动物、细胞和分子水平系统研究mPGES-2对DKD肾小管功能损伤和间质纤维化的作用及机制，为发现和确认治疗DKD药物新靶点提供理论支持。

Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease, but drugs which can treat DKD specifically do not currently exist. In the kidney, mPGES-2 is mainly expressed in renal tubular cells, and its study on DKD has not been reported. Our recent study found that mPGES-2 knockout in db/db mice significantly improved renal tubular injury and renal fibrosis, and significantly reduced the level of MDA in the kidney instead of PGE2. MDA is an iconic product of lipid peroxidation, which has been shown to inhibit the proteasome degradation of p53, but whether MDA regulates the protein stability of p53 is unclear. Further studies found that without affecting the mRNA content, the deletion of mPGES-2 in db/db mice significantly reduced the p53 protein content. Therefore, we hypothesizes that mPGES-2 may be involved in the occurrence and development of DKD renal interstitial fibrosis by inhibiting the proteasome degradation of p53 through the synthesis of MDA. This project intends to systematically study the effect and mechanism of mPGES-2 on renal tubular injury and interstitial fibrosis of DKD at the animal, cellular and molecular levels, so as to provide theoretical support for the discovery and confirmation of new therapeutic targets for DKD.