The GPX3‐VCAM1 Axis Gates Pro‐Fibrotic Tubule Cell Fate in Hyperuricemic Nephropathy
TL;DR
A genetically defined, multi‐hit mouse model that recapitulates the sustained hyperuricemia, metabolic dysregulation, and progressive fibrosis of human disease is established and glutathione peroxidase 3 (GPX3) is identified as a master regulator restraining precursor cell differentiation into Profib PT cells.
Abstract
ABSTRACT Hyperuricemia is a major driver of chronic kidney disease, yet the underlying intrarenal mechanisms remain unclear. Here, we establish a genetically defined, multi‐hit mouse model that recapitulates the sustained hyperuricemia, metabolic dysregulation, and progressive fibrosis of human disease. Using this model, we demonstrate that soluble uric acid activates the renal NLRP3 inflammasome and that its inhibition attenuates kidney injury. Single‐nucleus RNA sequencing revealed a distinct pro‐inflammatory and pro‐fibrotic proximal tubule cell population (Profib PT) marked by high VCAM1 expression, which is conserved in human kidney disease. Direct VCAM1 neutralization with antibodies attenuated renal fibrosis, validating its functional role. Mechanistically, we identify glutathione peroxidase 3 (GPX3) as a master regulator restraining precursor cell differentiation into Profib PT cells. GPX3 expression is suppressed in hyperuricemia, licensing this pathogenic transition; conversely, dietary selenium supplementation restored GPX3 activity, blocked Profib PT differentiation and VCAM1‐dependent macrophage adhesion, and ameliorated renal fibrosis. Our findings define the GPX3‐VCAM1 axis as a central regulatory node in hyperuricemic nephropathy and identify nutritional selenium repletion as a novel therapeutic strategy to intercept fibrosis.