p21-Activated Kinase 4 and Ischemic Acute Kidney Injury in Mice and Humans

作者：Hwang Chan Yu, Byeoung Hoon Chung, Y.G Kim, Yoonji Lee, Hyunchae Sim, Sangkyu Lee, Hong Pil Hwang, Hee Chul Yu, Seunggyu Jeon, Han‐Joo Maeng, Dongyun Shin, Kyung Pyo Kang, Seung‐Yong Seo, Eun Ju Bae, Byung‐Hyun Park · 发表于：Journal of the American Society of Nephrology · 年份：2025 · DOI：10.1681/asn.0000000649 · 被引用次数：9 · 研究领域：Acute Kidney Injury Research、Chronic Kidney Disease and Diabetes、Adenosine and Purinergic Signaling

Key Points p21-activated kinase 4 (PAK4) phosphorylates and inactivates GSH peroxidase 3 in the kidney after ischemia-reperfusion. Mice lacking PAK4 or treated with PAK4 proteolysis-targeting chimera were protected from kidney damage caused by ischemia-reperfusion injury. PAK4 expression in kidney tissues post-transplant inversely correlated with kidney function. Background AKI after ischemia-reperfusion remains a substantial perioperative challenge lacking effective treatment. p21-activated kinase 4 (PAK4), a downstream effector of Rho GTPase, has been explored in hepatic ischemia-reperfusion injury, but its role in renal ischemia-reperfusion is unknown. Methods Wild-type and proximal tubule–specific Pak4 knockout mice underwent 25 minutes of ischemia followed by 24 hours of reperfusion injury. Primary tubular cells and human kidney-2 cells were exposed to hypoxia-reoxygenation injury to investigate the in vitro effect of PAK4. Selective degradation of PAK4 was employed using proteolysis-targeting chimera (PROTAC) to ameliorate AKI. Results Post–ischemia-reperfusion, the expression of PAK4 was upregulated through hypoxia-inducible factor 1 α in mouse kidneys. Deletion of PAK4 in proximal tubule cells, but not in myeloid cells, significantly mitigated ischemia-reperfusion–induced AKI, as evidenced by decreased levels of BUN, creatinine, tubular necrosis, apoptosis, macrophage infiltration, and lipid accumulation compared with control mice. Further investigation revealed that ...