Remote Ischemic Preconditioning Attenuates Mitochondrial Dysfunction and Ferroptosis of Tubular Epithelial Cells by Inhibiting NOX4-ROS Signaling in Acute Kidney Injury.

Abstract

Acute kidney injury (AKI) is a worldwide clinical burden associated with high morbidity and mortality. Remote ischemic preconditioning (rIPC), a brief nonlethal ischemia and reperfusion (IR) in remote tissues or limbs, has been used in an attempt to protect against AKI, but its underlying signaling pathways has not been elucidated. In the present study, rIPC protected kidney function and pathological injury and mitigated NADPH oxidase 4 (NOX4) upregulation in different AKI models (cisplatin, LPS and IRI). Furthermore, rIPC significantly attenuated mitochondrial dysfunction and ameliorated tubular epithelial ferroptosis during AKI. Mechanistically, in wild-type AKI mice and TCMK-1 cells, rIPC effectively decreased kidney ROS production, preserved mitochondrial dynamics and mitophagy, and ameliorated tubular epithelial ferroptosis. Notably, these protective effects of rIPC were further enhanced by NOX4 knockout or silencing and mitigated by NOX4 overexpression. Our study showed that rIPC may attenuate mitochondrial dysfunction and ferroptosis in tubular epithelial cells in AKI by inhibiting NOX4-ROS signaling. NOX4 might be used as a biomarker for monitoring the biological effects of rIPC to optimize the rIPC protocol and facilitate future translational studies.