FNDC5/Irisin-Dependent Renoprotection of Resistance Training in Myocardial Infarction–Induced Type 2 Cardiorenal Syndrome

Type 2 cardiorenal syndrome (CRS), driven by chronic myocardial infarction (MI), has attracted increasing research attention due to its involvement in renal fibrosis and oxidative stress. However, the mechanisms underlying renal damage and potential rehabilitation strategies remain inadequately understood. This study aims to explore whether resistance exercise mitigates MI-induced renal dysfunction by regulating the FNDC5/Irisin axis. Using both wild-type and FNDC5/Irisin knockout mice, we established a Type 2 CRS model and implemented a resistance exercise intervention. In parallel, H ₂ O ₂ -stimulated HKC cells were used to construct an in vitro fibrosis model. We assessed renal injury, oxidative stress, fibrosis-related signaling (TGF-β1/Smad2/3), and the expression of key antioxidant and fibrotic markers. Our results demonstrated that resistance exercise significantly improved cardiac and renal function, reduced oxidative stress and collagen deposition, and inhibited TGF-β1–Smad2/3 activation. These effects were largely abrogated in Irisin-deficient mice. Additionally, rhIrisin and AICAR alleviated oxidative stress and fibrosis in vitro, confirming the functional role of Irisin. In conclusion, resistance exercise exerts renoprotective effects in Type 2 CRS through upregulation of FNDC5/Irisin, highlighting a novel therapeutic target and providing scientific support for exercise-based rehabilitation strategies in heart failure patients with renal involvement.