Irisin/PGC-1-α improves acute kidney injury by enhancing autophagy and regulating lipid metabolism.

Abstract

Acute kidney injury (AKI) is a critical clinical condition characterized by rapid loss of renal function and high morbidity. Irisin, a muscle-derived myokine, has been reported to exert protective effects in multiple tissues; however, its role in AKI remains largely unexplored. This study aimed to elucidate the renoprotective effects of irisin and its underlying mechanisms, with a particular focus on PGC-1α activation and autophagy regulation. Male C57BL/6 mice were subjected to lipopolysaccharide (LPS)–induced AKI and treated intravenously with irisin (10 mg/kg). Renal function, histopathological alterations, inflammatory markers, and apoptosis were assessed. In vitro, HK-2 cells were exposed to irisin, PGC-1α-specific siRNA, or the autophagy inhibitor chloroquine (CQ). Autophagic flux, lipid metabolism, mitochondrial function, and oxidative stress were subsequently evaluated. Irisin treatment markedly improved renal function in AKI mice by lowering serum creatinine and blood urea nitrogen levels, attenuating tubular injury, and suppressing inflammation and apoptosis. In HK-2 cells, irisin upregulated PGC-1α expression and enhanced autophagic activity, effects that were abolished by PGC-1α knockdown or CQ treatment. Additionally, irisin promoted lipid catabolism, reduced intracellular ROS accumulation, stabilized mitochondrial membrane potential, and protected cells from LPS-induced injury. Irisin alleviates AKI by activating PGC-1α–mediated autophagy, thereby mitigating inflammation, lipid accumulation, oxidative stress, and cellular damage. These findings highlight irisin as a potential therapeutic candidate for preventing or treating AKI.