毛细血管稀疏是肾间质纤维化发生发展的核心环节。如何通过改善毛细血管稀疏抑制肾间质纤维化是亟待解决的科学难题。前期研究发现，内皮祖细胞（EPCs）介导外泌体促进血管生成和结构稳定，抑制了肾间质纤维化。外泌体蛋白组学检测出多种血管通路相关蛋白，以Neuropilin-1（Nrp1）表达最高，推测EPCs可能通过外泌体介导Nrp1改善毛细血管稀疏从而抑制肾间质纤维化。本项目建立缺血再灌注损伤诱导的肾间质纤维化模型，拟从基因水平上调Nrp1的表达，增强EPCs促血管生成作用；在分子水平阻断Nrp1与受体细胞的结合，探讨EPCs参与血管生成和稳定的机制；并通过转录组学和蛋白组学，进一步分析EPCs介导Nrp1直接调控受体细胞参与血管生成和稳定作用的靶点，探索EPCs较传统血管生长因子治疗更具靶向性的作用机制，通过精准干预EPCs以实现更安全高效改善血管稀疏、增加肾脏血流灌注而防治肾间质纤维化的目标。

Capillary rarefaction is a key mechanism in the development of renal interstitial fibrosis (RIF), however the mechanism by which alleviation of capillary rarefaction attenuates RIF is still elusive. Our previous studies showed that endothelial progenitor cells (EPCs) promoted angiogenesis and sustained vascular structural stability through the secretion of exosomes, thereby improving capillary rarefaction and inhibiting RIF development. Proteomic analysis of EPCs-exosomes revealed that they contained a wide variety of angiogenesis-associated proteins, among which Neuropilin-1 (Nrp1) was the most highly expressed. We speculated that Nrp1 from EPCs-exosomes might regulate renal angiogenesis to alleviate RIF. In this project, an ischemia-reperfusion injury model will be implemented to induce RIF. Genetic modification of Nrp1 expression in EPCs will be performed to observe its effect on the pro-angiogenic function of EPCs. On the molecular level, Nrp1 binding to recipient cells will be selectively blocked to investigate the specific mechanism by which Nrp1 regulates angiogenesis and vascular stabilization. Furthermore, we will perform transcriptomic and proteomic analyses in order to further investigate how EPCs-derived Nrp1 directly regulates recipient cells to participate in angiogenesis and vascular stability, and understand how modified EPCs can be a safer therapeutic option than traditional vascular endothelial growth factor supplementation, thus offering increased efficiency of renal perfusion and prevent RIF by alleviating capillary rarefaction.