αKlotho modulates BNIP3-mediated mitophagy by regulating FoxO3 to decrease mitochondrial ROS and apoptosis in...

Area of Science:

• Nephrology
• Molecular Biology
• Cellular Biology

Background:

• Contrast-induced acute kidney injury (CI-AKI) is a significant cause of hospital-acquired renal failure with limited effective treatments.
• Alpha-Klotho (αKlotho), an anti-aging protein highly expressed in the kidney, has shown therapeutic potential in CI-AKI by enhancing autophagy.

Purpose of the Study:

• To elucidate the specific mechanism by which αKlotho promotes autophagy in the context of CI-AKI.
• To investigate the role of mitophagy and apoptosis in αKlotho's therapeutic effects on CI-AKI.

Main Methods:

• RNA sequencing analysis of renal cortex in αKlotho-treated and vehicle-treated CI-AKI mice.
• In vivo and in vitro experiments using CI-AKI mouse models and Iohexol-treated HK-2 cells.
• Investigation of the FoxO3-BNIP3 pathway, including gene knockdown and deletion studies.

Main Results:

• αKlotho treatment promoted mitophagy and reduced apoptosis in CI-AKI models.
• αKlotho attenuated mitochondrial damage and decreased mitochondrial reactive oxygen species (ROS) by upregulating BNIP3-mediated mitophagy.
• αKlotho upregulated FoxO3 nuclear expression, which was essential for BNIP3-mediated mitophagy and protection against oxidative injury and apoptosis.

Conclusions:

• αKlotho alleviates CI-AKI by promoting mitophagy through the FoxO3-BNIP3 pathway.
• The findings highlight a critical role for αKlotho in mitigating kidney damage in CI-AKI.
• Targeting the αKlotho-FoxO3-BNIP3 axis may offer a novel therapeutic strategy for CI-AKI.