Abstract：
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.
摘要：
缺氧诱导的炎症和细胞凋亡是中暑急性肾损伤(HS-AKI)的重要病理生理特征。缺氧诱导因子(HIF)是调节细胞适应缺氧的关键蛋白。HIF-脯氨酸酰羟化酶抑制剂(HIF-PHI)稳定HIF以增加细胞对缺氧的适应。在这里，我们报道HIF-PHI预处理显著改善肾功能,增强的耐热性，并提高了HS背景下小鼠的存活率。此外，HIF-PHI可以减轻HS诱导的线粒体损伤，炎症,在体外和体内增强线粒体自噬和肾小管上皮细胞（RTECs）的凋亡。相比之下,线粒体自噬抑制剂Mdivi-1，3-MA，和Baf-A1逆转HIF-PHI的肾脏保护作用。机械上,HIF-PHI通过增强Bcl-2腺病毒E1819-kDa相互作用蛋白3（BNIP3）介导的线粒体自噬来保护RTECs免受炎症和凋亡，而BNIP3的遗传消融减弱了HIF-PHI诱导的线粒体自噬并消除了HIF-PHI介导的肾保护作用。因此，我们的结果表明，HIF-PHI通过上调BNIP3介导的线粒体自噬来改善HS诱导的RTECs炎症和凋亡，从而保护肾功能，提示HIF-PHI是治疗HS-AKI的有前途的治疗剂。
