Uromodulin p.His36Tyr promotes macrophage pyroptosis via App-Cd74 signaling to drive renal inflammation in ADTKD

Abstract Autosomal dominant tubulointerstitial kidney disease -UMOD (ADTKD-UMOD) is characterized by progressive renal interstitial inflammation and fibrosis. However, its underlying mechanisms remain unclear. Here, we identify a large ADTKD pedigree harboring a novel UMOD p.H36Y mutation. Using CRISPR/Cas9 technology, we generated a UmodH36Y/+ mouse model that recapitulates the key phenotypes observed in affected individuals, including renal dysfunction, cyst formation, interstitial inflammation, and fibrosis. Multi-omics analyses revealed marked macrophage pyroptosis in UmodH36Y/+ kidneys. Treatment with disulfiram (DSF), a pyroptosis inhibitor, significantly alleviated interstitial inflammation and improved renal function. Mechanistically, the Umod p.H36Y variant activated the amyloid precursor protein (App)-Cd74 axis which mediated the crosstalk between renal TECs and macrophages. This axis sustains NF-κB pathway activation in macrophages, initiating pyroptosis and pro-inflammatory cytokine release. Disrupting App-Cd74 signaling effectively suppressed macrophage pyroptosis. Notably, pharmacologic inhibition using ARN2966, a small-molecule App inhibitor, markedly attenuated renal injury in UmodH36Y/+ mice. Collectively, these findings uncover a novel, targetable pathway in ADTKD-UMOD.