OXSR1 deficiency attenuates oxidative stress and tubular injury in ischemia-reperfusion-induced acute kidney injury via JAK2/STAT3 inactivation

Background Acute kidney injury (AKI) caused by ischemia-reperfusion injury (IRI) is a serious clinical problem characterized by renal tubular damage and elevated oxidative stress. OXSR1 expression is markedly upregulated in renal tubular epithelial cells during AKI, but its functional role and downstream signaling in IRI-induced AKI have not been elucidated. Methods We employed human proximal tubular epithelial HK-2 cells and C57BL/6J mouse model of IRI-induced AKI. Kidney-specific OXSR1 knockdown was achieved by serotype 9 adeno-associated virus (AAV9)-mediated short hairpin RNA (shRNA) delivery. Renal injury, oxidative stress and apoptosis were assessed after OXSR1 knockdown. Subsequently, RNA sequencing was employed to identify downstream pathways. Experiments involving IL-6 treatment and JAK2 overexpression were conducted to validate the downstream mechanisms. Results OXSR1 deficiency significantly attenuated oxidative stress, reduced tubular damage, and improved renal function in IRI mice. In HK-2 cells, OXSR1 knockdown alleviated hypoxia/reoxygenation (H/R)-induced apoptosis, oxidative stress and inflammation. IL-6 treatment and JAK2 overexpression reversed the protective effect of OXSR1 knockdown. Conclusion OXSR1 deficiency attenuated IRI-induced AKI via JAK2/STAT3 inactivation. OXSR1 may represent a potential target for alleviating oxidative stress-mediated renal tubular damage in IRI-induced AKI.