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

Abstract

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.

Keywords

• cGAS‐STING
• contrast‐induced acute kidney injury
• inflammation
• irisin
• mPGC‐1α