αKlotho modulates BNIP3-mediated mitophagy by regulating FoxO3 to decrease mitochondrial ROS and apoptosis in contrast-induced acute kidney injury

Contrast-induced acute kidney injury (CI-AKI) is one of the main causes of hospital-acquired renal failure, and still lacks of effective treatments. Previously, we demonstrated that αKlotho, which is an Anti-aging protein that highly expresses in the kidney, has therapeutic activity in CI-AKI through promoting Autophagy. However, the specific mechanism underlying αKlotho-mediated Autophagy remains unclear. The RNA Sequencing analysis of renal cortex revealed that the differentially expressed genes related to Autophagy between αKlotho-treated CI-AKI mice and vehicle-treated CI-AKI mice were found to be associated with Mitophagy and Apoptosis. In the kidney of CI-AKI mice and HK-2 cells exposed to Iohexol, we revealed that αKlotho promoted Mitophagy and decreased cell Apoptosis. Mechanistically, αKlotho attenuated mitochondria damage, decreased mitochondrial ROS by upregulating BNIP3-mediated Mitophagy. BNIP3 deletion abolished the beneficial effects of αKlotho both in vivo and in vitro. Moreover, we further demonstrated that αKlotho upregulated FoxO3 nuclear expression in Iohexol-treated HK-2 cells. Knockdown of FOXO3 gene inhibited αKlotho-promoted BNIP3-mediated Mitophagy and subsequently increased the oxidative injury and cell Apoptosis. Taken together, our results indicated a critical role of αKlotho in alleviating CI-AKI via Mitophagy promotion involving the FoxO3-BNIP3 pathway.

Acute kidney injury; Contrast media; FoxO3; Klotho; Mitophagy.