Intermedin protects peritubular capillaries by inhibiting eNOS uncoupling through AMPK/GTPCH-I/BH4 pathway and alleviate CKD following AKI

作者：Hui Lin, Juan Pan, Junhua Zhang, Ye He, Ge Yuan, Dan Niu, Weixia Han, Xiaoli Han, Li Fan, Xiaomei Bai, Xinyuan Feng, Ling Lin, Ruihua Shen, Xiaole Su, Xi Qiao · 发表于：Free Radical Biology and Medicine · 年份：2025 · DOI：10.1016/j.freeradbiomed.2025.04.015 · 被引用次数：8 · 研究领域：Cardiac Fibrosis and Remodeling、Adipokines, Inflammation, and Metabolic Diseases、Atherosclerosis and Cardiovascular Diseases

Background Even after recovery of kidney function following AKI , progression to CKD may still occur, characterized by a reduction in peritubular capillaries (PTC) and subsequent kidney fibrosis . Reactive oxygen species (ROS) from uncoupled eNOS are suspected to damage endothelial cells and cause PTC rarefaction observed in AKI-CKD. Intermedin (IMD) inhibits eNOS uncoupling by activating AMPK , but its impact on AKI-CKD transition remains unclear. Methods We utilized IMD-deficient (IMD −/− ) mice to explore its effects on AKI-CKD transition, PTC density, endothelial damage, and kidney ROS in a kidney ischemia/reperfusion injury (IRI) model. To elucidate its protective mechanism for PTCs, we subsequently investigated the effects of IMD on endothelial cells and ROS using a hypoxia/reoxygenation (HR) model with human umbilical vein endothelial cells (HUVECs). Finally, we investigated the influence of IMD on AMPK/GTPCH-I/BH4/eNOS to explore its mechanism in alleviating oxidative stress . Results Compared with IMD +/+ littermate sham controls, PTC density was significantly reduced in IMD −/− sham mice, with significantly increased oxidative stress . Post-AKI, both IMD +/+ and IMD −/− mice demonstrated substantial declines in kidney function and histology, along with significant fibrosis, PTC reduction, and heightened oxidative stress. Moreover, the severity of kidney damage in IMD −/− mice following AKI was considerably more pronounced than in IMD +/+ mice. HR significantly induc...