SENP1通过HIF1α调控巨噬细胞极化在缺血再灌注肾损伤中的作用及机制

Hypoxic injury and inflammation play a critical role in the pathogenesis of renal ischemia-reperfusion (IR) injury. It has been reported that macrophage is among the key immune cells participating in the inflammation of IR injury. However, it has not been documented before whether hypoxia could regulate macrophage activity and induce inflammation. Preliminary study confirmed that SUMO-specific protease 1 (SENP1), a major regulatory factor of hypoxia-inducible factor-1α (HIF1α), levels increased after IR in mice kidney. Employing LyzCre+SENP1-/- mice, we found that SENP1 knockout reduced renal IR injury. Therefore, we speculate that there is a regulatory relationship between SENP1 and HIF1α in macrophage, which affects the activity of specific macrophage subpopulations as well as the renal pathological process of under IR. This study will focus on the following: 1) What is the regulatory relationship between SENP1 and macrophage activity in renal IR injury? 2) Whether does SENP1 regulate macrophage activity via hypoxia signaling pathway mediated HIF1α? 3) What is the relationship between SENP1 level change in IR and renal pathological process? This study may further disclose the mechanism of inflammation in IR, and also, may lead to new therapeutic protocols to alleviate acute kidney injury.

缺氧损伤和炎症反应是缺血再灌注（IR）肾损伤的重要发病机制。研究表明，巨噬细胞是参与IR炎症反应的关键细胞之一。然而IR过程中缺氧反应是否调控巨噬细胞活性，进而引起炎症反应尚无报道。预实验中本课题组发现，IR损伤的肾组织中，缺氧诱导因子（HIF1α）的重要调控因子去SUMO化修饰蛋白酶1（SENP1）表达增加。巨噬细胞特异性敲除SENP1可减轻IR肾损伤。因此，我们推测SENP1通过HIF1α介导的缺氧信号调控巨噬细胞的活化，并影响肾IR的病理过程。本项目将重点研究如下问题：1）SENP1在肾IR引起的巨噬细胞活化过程中的调控作用？ 2）SENP1是否通过HIF1α介导的缺氧信号通路调控巨噬细胞活化？3）SENP1在肾IR过程中的动态变化及与IR病理过程的关系？通过对以上问题的研究，能够帮助我们进一步了解IR中炎症反应发生机制，有可能为急性肾损伤的防治寻找到新的靶点。

缺氧损伤和炎症反应是缺血再灌注(IR)肾损伤的重要发病机制。研究表明，巨噬细胞是参与IR炎症反应的关键细胞之一。然而IR过程中缺氧反应是否调控巨噬细胞活性，进而引起炎症反应尚无报道。本课题，通过体内和体外实验，从以下三个方面进行讨论：1)SENP1在肾IR引起的巨噬细胞活化过程中的调控作用? 2)SENP1是否通过HIF1α介导的缺氧信号通路调控巨噬细胞活化?3)SENP1在肾IR过程中的动态变化及与IR病理过程的关系?证实SENP1通过HIF1α介导的缺氧信号调控巨噬细胞的活化，并影响肾IR的病理过程。本研究能够帮助我们进一步了解IR中炎症反应发生机制，为急性肾损伤的防治寻找到新的靶点。