NOX4 mediates the renoprotection of remote ischemic preconditioning against acute kidney injury by inhibiting NF-κB signaling and tubular apoptosis.

Acute kidney injury (AKI) is a clinical syndrome characterized by an abrupt loss of kidney function and is associated with increased morbidity and mortality. Remote ischemic preconditioning (rIPC) is a nonpharmacological intervention involving brief episodes of ischemia in distal tissues, which may provide protection from kidney injury, but its underlying mechanism remain elusive. In a previous study, we demonstrated that NOX4 can serve as a potential therapeutic target in AKI and is associated with the upregulation of inflammation and apoptosis. Therefore, we hypothesized that rIPC might attenuate AKI by inhibiting the NOX4-mediated NF-κB signaling pathway and apoptosis. In this study, we demonstrated that rIPC protected kidney function and pathological injury in lipopolysaccharide (LPS)-induced, cisplatin-induced and ischemic-reperfusion injury (IRI)-induced AKI mouse models. rIPC significantly inhibited the activation of NF-κB and tubular epithelial apoptosis in AKI mice, and hypoxic preconditioning (HPC) similarly suppressed NF-κB and apoptosis of TCMK-1 cells. Notably, rIPC intervention alone slightly increased/preconditioned NOX4 expression in control group mice, while substantially inhibiting NOX4 overexpression when the mice were subjected to AKI insults. Mechanistically, In LPS-stimulated TCMK-1 cells overexpressing NOX4, when treated with rIPC, the excessive activation of NF-κB and apoptosis was further alleviated. These findings demonstrated that rIPC is a potential therapeutic method against AKI and that NOX4 plays a central role in mediating the protective effects of rIPC through the inhibition of NF-κB signaling and tubular apoptosis.