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.

BNIP3; HIF‐PHI; acute kidney injury; heat stroke; mitophagy.