KDM1A regulates nephron progenitor programs and is associated with human kidney disease risk

BACKGROUND: Genome-wide association studies (GWAS) have identified numerous loci associated with kidney function, but linking non-coding variants to causal effector genes remains challenging. By integrating fine-mapped GWAS data from 2.27 million individuals with kidney expression and epigenomic datasets, we identified KDM1A as a top-prioritized gene at a kidney function locus. KDM1A is broadly expressed across nephron segments in mouse and human kidneys and is consistently upregulated in chronic kidney disease (CKD). METHODS: We generated lineage-specific Kdm1a knockout mice targeting nephron progenitors (Six2-Cre) or differentiated tubular epithelial cells (Cdh16/Ksp1-Cre). Renal structure and function were assessed at baseline and following adenine-induced injury or unilateral ureteral obstruction using histology, immunoblotting, and gene expression analyses. Pharmacologic inhibition of KDM1A was evaluated in embryonic kidney explant cultures. RESULTS: Nephron progenitor-specific deletion of Kdm1a resulted in severe developmental defects, including nephron loss, cystic degeneration, tubular atrophy, and early interstitial fibrosis. Mutant kidneys exhibited suppression of progenitor and segment-specific epithelial programs, loss of solute transporter expression, and derepression of developmental signaling pathways, including Notch and Wnt, accompanied by apoptosis and inflammation. In contrast, deletion of Kdm1a in differentiated tubular epithelial cells preserved baseline renal structure and function and did not modify fibrotic responses to injury. Pharmacologic inhibition of KDM1A during kidney development phenocopied genetic loss and led to accumulation of H3K4 methylation. CONCLUSIONS: KDM1A is a genetically supported, developmentally essential chromatin regulator required for nephron differentiation but dispensable in differentiated tubular epithelium. Its reactivation in CKD highlights a context-dependent epigenetic role and cautions against nonspecific KDM1A inhibition.