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

Aims: 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. Results: In the present study, an in vivo 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 in vitro significantly increased BNIP3, autophagy and ER degradation, whereas inhibition of BNIP3 significantly reversed the effects of HIF-1α. In addition, the in vitro 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 in vitro. Innovation and Conclusion: These data indicate that HIF-1α/BNIP3-mediated ER degradation via autophagy in tubular cells protects against IR-induced AKI. Antioxid. Redox Signal. 42, 212-227.