GPR183 contributes to renal macrophage infiltration and fibrosis in kidney injury.

Macrophages play a key role in kidney inflammation and fibrosis. The oxysterol receptor G protein-coupled receptor 183 (GPR183) is an important immunomodulatory receptor, but its role in kidney disease is undefined. In this study, we investigated the contribution of GPR183 to renal injury using adenine diet-induced chronic kidney disease and folic acid-induced nephropathy models. Both models exhibited marked upregulation of the cholesterol hydroxylases CH25H and CYP7B1, along with increased GPR183 expression in the kidney. Immunofluorescence analysis demonstrated that GPR183 colocalized with M1 macrophage markers within injured kidneys. Genetic deletion of GPR183 selectively reduced renal M1 macrophage accumulation and proinflammatory cytokine expression without affecting M2 macrophage infiltration, leading to improved renal function. GPR183 deficiency also significantly attenuated renal fibrosis, as evidenced by decreased collagen deposition and reduced expression of fibronectin and α-smooth muscle actin. In primary bone marrow-derived macrophages, GPR183 deletion suppressed lipopolysaccharide (LPS) and interferon γ (IFN-γ)-induced M1 polarization through inhibition of NF-κB signaling. Finally, analysis of publicly available human single-cell RNA sequencing data demonstrated substantial GPR183 expression in immune cells, including macrophages, in patients with chronic kidney disease. These findings identify GPR183 as a key regulator of macrophage phenotype in kidney injury and demonstrate that activation of the oxysterol-GPR183 axis promotes inflammatory and fibrotic renal remodeling. Targeting GPR183 may therefore represent a novel therapeutic strategy for the treatment of progressive kidney disease.NEW & NOTEWORTHY This study identifies GPR183 as a previously unrecognized regulator of macrophage polarization and renal fibrogenesis. We demonstrate that kidney injury activates an oxysterol-GPR183 signaling axis that promotes NF-κB-dependent M1 macrophage polarization. Genetic deletion of GPR183 selectively limits inflammatory macrophage accumulation, attenuates fibrosis, and preserves renal function, establishing GPR183 as a novel therapeutic target in progressive kidney disease.