Type 2 cardiorenal syndrome (CRS), driven by chronic myocardial infarction (MI), is characterized by renal fibrosis and oxidative stress, yet underlying mechanisms and therapies are poorly defined. This study investigated whether resistance training protects against MI-induced renal injury via the FNDC5/Irisin axis. Male wild-type (WT) and global Fndc5 knockout (KO) mice were subjected to MI or sham surgery and then allocated to sedentary or ladder-climbing resistance training groups for 4 weeks (n = 8 per group). An in vitro model was established using H2O2-stimulated human renal tubular (HKC) cells. We found that resistance training upregulated renal FNDC5 expression, lowered serum creatinine and blood urea nitrogen levels, and attenuated tubular injury in WT mice with CRS, but these benefits were markedly blunted in KO mice. Training reduced renal malondialdehyde content, enhanced superoxide dismutase 1/2 expression, and decreased collagen deposition alongside downregulation of fibrotic markers (Collagen-I/III, α-SMA). These improvements were associated with suppressed activation of the renal TGF-β1/Smad2/3 pathway in WT but not in KO mice. In HKC cells, recombinant Irisin and the AMPK agonist AICAR mitigated H2O2-induced oxidative stress, fibrotic protein expression, and Smad2/3 phosphorylation. We conclude that resistance exercise ameliorates renal oxidative stress and fibrosis in Type 2 CRS, effects that are substantially mediated by, but not exclusively dependent on, the FNDC5/Irisin axis. Our work highlights FNDC5/Irisin as a key amplifier of exercise-induced renoprotection and supports the therapeutic potential of resistance training in cardiorenal syndrome.
Copyright: © 2026 Fu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.