Regulation of mitophagy through HIF-1α/miR-140-5p/PARKIN axis in acute kidney injury.

Abstract

Mitochondria homeostasis plays an important role in acute kidney injury (AKI). In this study, we aimed at identifying the mechanism of mitophagy regulation in AKI. Activation of mitophagy after ischemic kidney injury was visualized with increased expression of LC3, PINK1, PARKIN expression and with a subsequent decline in p62 levels. Immuohistochemistry staining showed higher LC3 levels in ischemic kidney injury mice. Further, differential expression of PARKIN targeting miRNAs revealed that miR-140-5p was significantly downregulated followed by ischemic kidney injury. miR-140-5p mimics suppressed PARKIN expressions and their mitochondrial translocation. Further, miR-140-5p mimics under hypoxia prevented mitophagosome formation. These effects on hypoxia-induced PARKIN expression and LC3/TOMM20 levels were reversed by antagomiR miR-140-5p treatment. Dual-luciferase reporter assay revealed that miR-140-5p had significant interaction with 3'UTR of PARKIN. Our findings show that HIF-1α is bound to miR-140-5p promoter and down regulates its expression and thereby promotes mitophagy process under hypoxic conditions. These results cumulatively show that HIF-1α regulates mitophagy during AKI through the regulation of miR-140-5p/PARKIN axis.