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

Resistance training upregulated renal FNDC5 expression in wild-type mice with cardiorenal syndrome.

• Male wild-type (WT) and global Fndc5 knockout (KO) mice were subjected to MI or sham surgery
• Animals were allocated to sedentary or ladder-climbing resistance training groups for 4 weeks
• Sample size was n=8 per group
• Renal FNDC5 upregulation was observed in WT mice but the model employed KO mice to test dependence on this pathway

Resistance training lowered serum creatinine and blood urea nitrogen levels and attenuated tubular injury in WT mice with cardiorenal syndrome.

• These renoprotective benefits were markedly blunted in Fndc5 knockout mice
• The model used myocardial infarction-induced Type 2 cardiorenal syndrome in male mice
• Training duration was 4 weeks using a ladder-climbing protocol
• Tubular injury was assessed histologically alongside functional markers

Resistance training reduced renal oxidative stress markers in WT but not Fndc5 KO mice.

• Training reduced renal malondialdehyde (MDA) content
• Training enhanced superoxide dismutase 1 and 2 (SOD1/2) expression
• These antioxidant effects were markedly blunted in KO mice
• Findings indicate FNDC5/Irisin mediates a substantial portion of exercise-induced antioxidant protection in the kidney

Resistance training decreased renal collagen deposition and downregulated fibrotic markers in WT mice, effects blunted in Fndc5 KO mice.

• Fibrotic markers assessed included Collagen-I, Collagen-III, and α-SMA
• Collagen deposition was evaluated alongside fibrotic protein expression
• These anti-fibrotic improvements were markedly blunted in KO mice
• Results implicate FNDC5/Irisin as a key mediator of exercise-induced renal anti-fibrotic effects

Resistance training suppressed activation of the renal TGF-β1/Smad2/3 signaling pathway in WT but not Fndc5 KO mice.

• TGF-β1/Smad2/3 pathway activation was assessed in renal tissue
• Pathway suppression was observed in WT mice following resistance training
• This suppression was absent in Fndc5 KO mice, linking FNDC5/Irisin to pathway regulation
• TGF-β1/Smad2/3 is a canonical pathway driving renal fibrosis

Recombinant Irisin and the AMPK agonist AICAR mitigated H2O2-induced oxidative stress, fibrotic protein expression, and Smad2/3 phosphorylation in human renal tubular (HKC) cells.

• An in vitro model was established using H2O2-stimulated human renal tubular (HKC) cells
• Both recombinant Irisin and AICAR (AMPK agonist) were tested
• Outcomes measured included oxidative stress markers, fibrotic protein expression, and Smad2/3 phosphorylation
• Results suggest the FNDC5/Irisin axis acts at least partly through AMPK signaling to suppress TGF-β1/Smad2/3 activity

FNDC5/Irisin was identified as a key amplifier of exercise-induced renoprotection but renoprotective effects of resistance training were not exclusively dependent on it.

• Renoprotective benefits were 'markedly blunted' rather than completely abolished in KO mice
• The authors conclude effects are 'substantially mediated by, but not exclusively dependent on, the FNDC5/Irisin axis'
• This indicates other mechanisms beyond FNDC5/Irisin also contribute to exercise-induced renoprotection
• The study supports the therapeutic potential of resistance training in cardiorenal syndrome