Hypoxia‐inducible factor prolyl hydroxylase inhibitor alleviates heatstroke‐induced acute kidney injury by activating BNIP3‐mediated mitophagy

Hypoxia‐induced inflammation and apoptosis are important pathophysiological features of heat stroke‐induced acute kidney injury (HS‐AKI). Hypoxia‐inducible factor (HIF) is a key protein that regulates cell adaptation to hypoxia. HIF‐prolyl hydroxylase inhibitor (HIF‐PHI) stabilizes HIF to increase cell adaptation to hypoxia. Herein, we reported that HIF‐PHI pretreatment significantly improved renal function, enhanced thermotolerance, and increased the survival rate of mice in the context of HS. Moreover, HIF‐PHI could alleviate HS‐induced mitochondrial damage, inflammation, and apoptosis in renal tubular epithelial cells (RTECs) by enhancing mitophagy in vitro and in vivo. By contrast, mitophagy inhibitors Mdivi‐1, 3‐MA, and Baf‐A1 reversed the renoprotective effects of HIF‐PHI. Mechanistically, HIF‐PHI protects RTECs from inflammation and apoptosis by enhancing Bcl‐2 adenovirus E18 19‐kDa–interacting protein 3 ( BNIP3 )‐mediated mitophagy, while genetic ablation of BNIP3 attenuated HIF‐PHI‐induced mitophagy and abolished HIF‐PHI‐mediated renal protection. Thus, our results indicated that HIF‐PHI protects renal function by upregulating BNIP3 ‐mediated mitophagy to improve HS‐induced inflammation and apoptosis of RTECs, suggesting HIF‐PHI as a promising therapeutic agent to treat HS‐AKI.