HIF-1α/BNIP3-Mediated Endoplasmic Reticulum Degradation via Autophagy Protects Against Ischemia Reperfusion-Induced Acute Kidney Injury

<b><i>Aims:</i></b> Endoplasmic reticulum (ER) degradation via autophagy is a process that maintains ER homeostasis when cells are in a state of stress and is associated with many diseases; however, the role of hypoxia inducible factor-1α (HIF-1α)-mediated ER degradation and the related regulatory pathway in acute kidney injury (AKI) still needs to be further established. <b><i>Results:</i></b> In the present study, an <i>in vivo</i> AKI model was induced in mice via the ischemia-reperfusion (IR) method. The results revealed that HIF-1α and BNIP3 were increased, and autophagy and ER degradation were activated in the kidneys of AKI mice, whereas HIF-1α knockout significantly inhibited BNIP3, autophagy and ER degradation, accompanied by aggravated kidney injury. Overexpression of HIF-1α <i>in vitro</i> significantly increased BNIP3, autophagy and ER degradation, whereas inhibition of BNIP3 significantly reversed the effects of HIF-1α. In addition, the <i>in vitro</i> inhibition of autophagy with chloroquine significantly reversed the effects of HIF-1α on cell apoptosis. Moreover, selectively overexpressing BNIP3 on the ER membrane significantly increased ER degradation via autophagy and decreased cell apoptosis <i>in vitro</i>. <b><i>Innovation and Conclusion:</i></b> These data indicate that HIF-1α/BNIP3-mediated ER degradation via autophagy in tubular cells protects against IR-induced AKI. <i>Antioxid. Redox Signal.</i> 42, 212-227.