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

作者：Baihai Jiao, Changlong An, Hao Du, Melanie Tran, Duomeng Yang, Yuqi Zhao, Penghua Wang, Zhaoyong Hu, Dong Zhou, Yanlin Wang · 发表于：British Journal of Pharmacology · 年份：2025 · DOI：10.1111/bph.17412 · 被引用次数：37 · 研究领域：interferon and immune responses、Immune responses and vaccinations、IL-33, ST2, and ILC Pathways

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 r...