# FNDC5/Irisin-dependent renoprotection of resistance training in myocardial infarction–induced Type 2 cardiorenal syndrome

## TL;DR

Resistance training helps protect the kidneys in a type of heart-kidney disease, and this benefit is partly due to a protein called Irisin.

## Contribution

This study shows that resistance training protects the kidneys in heart-induced kidney disease via the FNDC5/Irisin pathway.

## Key findings

- Resistance training reduced kidney damage and oxidative stress in mice with heart disease.
- The protective effects were reduced in mice lacking the FNDC5 gene.
- Irisin and AICAR reduced oxidative stress and fibrosis in kidney cells in the lab.

## Abstract

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.