Irisin‐mediated muscle‐renal crosstalk as a protective mechanism against contrast‐induced acute kidney injury via cGAS‐STING signalling inhibition

Abstract

BACKGROUND: Contrast-induced acute kidney injury (CI-AKI) continues to pose a pressing clinical challenge during invasive cardiovascular procedures due to the limited availability of preventative strategies. We aimed to demonstrate that irisin, a myokine induced by exercise, protects against CI-AKI by inhibiting the cGAS-STING inflammatory pathway. METHODS AND RESULTS: We explored the relationship between serum irisin levels and CI-AKI incidence in patients administered the contrast media iohexol. Notably, lower serum irisin levels were strongly associated with an increased incidence of CI-AKI following contrast media administration. To establish a causal link between serum irisin levels and CI-AKI, we utilised a mouse model that simulates exercise by overexpressing muscle-specific PGC-1α. This approach showed a significant reduction in tubular injury and mitochondrial dysfunction induced by iohexol via cGAS/STING suppression, thereby diminishing inflammation. Mechanistically, irisin was found to inhibit the activation of cGAS/STING, preventing double stranded DNA (dsDNA) leakage and reducing inflammation in tubular epithelial cells (TECs). Pharmacological inhibition of STING further corroborated these observations. Moreover, we identified integrin complex αV/β5 as the irisin receptor on TECs, which is essential for irisin-mediated suppression of cGAS-STING signalling and resolution of inflammation. CONCLUSIONS: Our data position irisin as a crucial factor in muscle‒kidney crosstalk, inhibiting cGAS-STING signalling and preventing dsDNA leakage via integrin αV/β5 in TECs, thus mitigating tubular injury and inflammation. These data underscore the potential of irisin as both a predictive biomarker for CI-AKI and a promising candidate for preventative strategies against CI-AKI. HIGHLIGHTS: Irisin mediated muscle-kidney crosstalk mitigated tubular injury and inflammation. Irisin inhibited the cGAS-STING signalling activation via integrin αV/β5 in tubular epithelial cells. Irisin was a predictive biomarker and a promising candidate for CI-AKI.