Affiliation:
1. Division of Nephrology, Department of Medicine The Fifth Affiliated Hospital Sun Yat‐Sen University Zhuhai China
2. Guangdong Provincial Engineering Research Center of Molecular Imaging Center The Fifth Affiliated Hospital Sun Yat‐Sen University Zhuhai China
3. Division of Nephrology, Department of Medicine The Third Affiliated Hospital of Sun Yat‐Sen University Zhuhai China
Abstract
Ischemia/reperfusion (I/R)‐induced acute kidney injury (AKI) is a common clinical syndrome with high morbidity and mortality. Ferroptosis, a newly discovered form of oxidative cell death, is involved in the pathogenesis of renal I/R injury; however, the underlying mechanism remains to be explored. Here, we reported that site 1 protease (S1P) promotes ischemic kidney injury by regulating ferroptotic cell death of tubular epithelial cells. S1P abundance was measured in hypoxia/reoxygenation (H/R)‐treated Boston University mouse proximal tubular (BUMPT) cells and I/R‐induced murine kidney tissue. S1P expression in BUMPT cells and kidneys was initially activated by hypoxic stimulation, accompanied by the ferroptotic response. Blocking S1P blunted H/R‐induced ferroptotic cell death, which also restored sirtuin 3 (SIRT3) expression and superoxide dismutase 2 (SOD2) activity in BUMPT cells. Next, inhibition of S1P expression restored I/R‐suppressed SIRT3 abundance, SOD2 activity and reduced the elevated level of mitochondria reactive oxygen species (mtROS), which attenuated tubular cell ferroptosis and renal I/R injury. In conclusion, S1P promoted renal tubular epithelial cell ferroptosis under I/R status by activating SIRT3‐SOD2‐mtROS signaling, thereby accelerating kidney injury. Thus, targeting S1P signaling may serve as a promising strategy for I/R kidney injury.
Subject
Cell Biology,Molecular Biology,Biochemistry