Genetic deficiency or pharmacological inhibition of cGAS–STING signalling suppresses kidney inflammation and fibrosis

Abstract Background and Purpose Chronic kidney disease (CKD) is characterised by inflammation, which can lead to tubular atrophy and fibrosis. The molecular mechanisms are not well understood. In this study, we investigated the functional role of the cyclic GMP–AMP synthase (cGAS)– stimulator of interferon genes (STING) signalling in renal inflammation and fibrosis. Experimental Approach Mice with global cGAS deficiency or global or myeloid cell‐specific STING deficiency or wild‐type mice treated with RU.521, a selective cGAS inhibitor, were used to examine the role of cGAS–STING signalling in renal inflammation and fibrosis in a preclinical model of obstructive nephropathy in vivo. Bone marrow‐derived macrophages were used to determine whether tubular epithelial cell‐derived DNA can activate cGAS–STING signalling in vitro. Key Results Following obstructive injury, cGAS–STING signalling was activated in the kidneys during the development of renal fibrosis. Mice with deficiency of cGAS or STING exhibited significantly less macrophage proinflammatory activation, myofibroblast formation, total collagen deposition, and extracellular matrix (ECM) protein production in the kidneys following obstructive injury. Pharmacological inhibition of cGAS with RU.521 reduced macrophage proinflammatory activation, suppressed myofibroblast formation, and attenuated kidney fibrosis following obstructive injury. Mechanistically, cGAS–STING signalling in macrophages is activated by double‐stranded DNA released from damaged tubular epithelial cells, which induces inflammatory responses. Conclusions and Implications Our study identifies the cGAS–STING signalling pathway as a critical regulator of macrophage proinflammatory activation during the development of renal fibrosis. Therefore, inhibition of cGAS–STING signalling may represent a novel therapeutic strategy for CKD.