Hypoxia-inducible factor prolyl hydroxylase inhibitor alleviates heatstroke-induced acute kidney injury by activating BNIP3-mediated mitophagy.
Ling WangYongwei SongPan ZhangWen-Ting ChenFei XiaoPing ZhouXue-Sen YangHuanzi DaiPublished in: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (2024)
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.
Keyphrases
- oxidative stress
- endothelial cells
- high glucose
- diabetic rats
- acute kidney injury
- endoplasmic reticulum stress
- cell cycle arrest
- single cell
- cell death
- magnetic resonance imaging
- nlrp inflammasome
- type diabetes
- genome wide
- dna methylation
- computed tomography
- bone marrow
- amino acid
- skeletal muscle
- subarachnoid hemorrhage
- cell proliferation
- heat shock protein