GPR108 deficiency promotes urate-induced renal interstitial fibrosis.

Uric acid, a product of purine metabolism, is predominantly excreted via the kidneys. Chronic hyperuricemia, often driven by high-purine diets, contributes to renal injury marked by inflammation, tubular damage, and interstitial fibrosis with epithelial-mesenchymal transition (EMT). G protein-coupled receptor 108 (GPR108), a negative regulator of NF-κB-mediated inflammation, remains unexplored in hyperuricemia-induced chronic kidney disease (CKD). This study investigates GPR108's role in uric acid nephropathy using adenine-fed mice and in vitro models. Gpr108-deficient mice exhibited aggravated renal fibrosis, EMT activation, and elevated cytokine levels compared to controls. In vitro, renal tubular epithelial cells of primary cultured Gpr108 knockout mice heightened sensitivity to uric acid-induced EMT, accompanied by increased TGF-β1 production and NF-κB activation. These findings demonstrate that GPR108 deficiency exacerbates renal inflammation and fibrosis by amplifying NF-κB-driven EMT and TGF-β1 signaling. Our study identifies GPR108 as a protective modulator in hyperuricemia-induced CKD, highlighting its potential as a therapeutic target to mitigate renal interstitial fibrosis.