Chronic kidney disease affects approximately 14.3% of people worldwide. Tubulointerstitial
fibrosis is the final stage of almost all progressive CKD. To date, the pathogenesis of renal
fibrosis remains unclear, and there is a lack of effective treatments, leading to
renal replacement therapy. Mitophagy is a type of selective autophagy that has been recognized as an important way to remove dysfunctional mitochondria and abrogate the excessive accumulation of mitochondrial-derived
reactive oxygen species (ROS) to balance the function of cells. However, the role of mitophagy and its regulation in renal
fibrosis need further examination. In this study, we showed that mitophagy was induced in renal tubular epithelial cells in renal
fibrosis. After silencing BNIP3, mitophagy was abolished in vivo and in vitro, indicating the important effect of the BNIP3-dependent pathway on mitophagy. Furthermore, in unilateral
ureteral obstruction (UUO) models and hypoxic conditions, the production of mitochondrial ROS, mitochondrial damage, activation of the NLRP3
inflammasome, and the levels of αSMA and TGFβ1 increased significantly following BNIP3 gene deletion or silencing. Following silencing BNIP3 and pretreatment with
mitoTEMPO or
MCC950, the
protein levels of αSMA and TGFβ1 decreased significantly in HK-2 cells under hypoxic conditions. These findings demonstrated that HIF1α-BNIP3-mediated mitophagy played a protective role against
hypoxia-induced renal epithelial cell injury and renal
fibrosis by reducing mitochondrial ROS and inhibiting activation of the NLRP3
inflammasome.