ELA在糖尿病肾小球内皮损伤中的保护作用及机制

肾小球内皮细胞损伤是糖尿病肾病微量蛋白尿产生的早期关键病理事件。ELA是G蛋白偶联受体APJ的新型内源性肽类配体，主要在肾脏表达。申请人前期研究发现，通过对糖尿病大鼠肾动脉转染过表达ELA质粒，可显著减少大鼠尿微量蛋白，恢复肾小球内皮细胞紧密连接功能，减少细胞粘附分子和炎症因子表达。本项目是前期发现的深入拓展，将研究糖尿病动物模型下肾脏ELA表达的时空变化，通过ELA敲降、过表达和治疗性输入ELA肽段等多手段进一步评估ELA对糖尿病肾小球内皮的保护作用。机制上，我们检测了肾小球内皮细胞在糖尿病前后以及使用ELA治疗后转录组的变化，明确可能受到ELA调控的主要分子通路。另外，在前期研究基础上，本项目还将进一步明确ELA、APJ、NLRP3及其上游调控分子、肾小球内皮细胞功能之间的关系。该课题的完成不仅能揭示ELA这一活性肽在糖尿病肾病中的作用机制，还能为糖尿病肾损伤的治疗提供新颖的靶点。

Glomerular endothelial cells injury represents the early predominant pathological events of glomerular filtration barrier damage and albuminuria during diabetes. ELA, a novel endogenous ligand for APJ receptor，expressed abundantly in adult kidney. Our previous work has confirmed that ELA treatment attenuated diabetes induced albuminuria, alleviated tight junction dysfunction, diminished production of adhesive and inflammatory molecules. In hence, we speculate that ELA may play crucial role in diabetic glomerular endothelial cells injury, which may need further exploration. In this project, we will try to validate the hypothesis via utilizing ELA heterozygous mice as well as ELA overexpression plasmid transfection or ELA peptide treatment. Mechanistically, we will find the potential molecular pathway via RNA-seq detection in glomerular endothelial cells with or without administration of high glucose and ELA. Furthermore, we will explore the relationship between ELA, APJ, NLRP3 and upstream molecules and Glomerular endothelial protection. In summary, the current study tries to elucidate the role of ELA in diabetic albuminuria and the underlying mechanisms and hopefully provides new target for the treatment of DKD.