Context-Dependent Role of Lysine-Specific Demethylase 1A in Kidney Development and Diseases

Background: Genetics and epigenetic factors shape kidney disease development. Here, we explored genome-wide association studies (GWAS) to identify epigenetic regulators linked to kidney dysfunction and prioritized Lysine-specific demethylase 1A (KDM1A), a histone demethylase involved in critical epigenetic regulation, as a strong candidate gene warranting thorough investigation due to its potential therapeutic implications in chronic kidney disease. Methods: We leveraged human kidney expression and methylation quantitative trait loci (eQTL, meQTL), and single-cell open chromatin and gene expression data to prioritize Kdm1A on chromosome 1 as a likely causal gene influencing kidney disease. KDM1A selectively demethylates histone H3 lysine residues at positions 4 or 9. Total kidney-specific (Six2-cre) and tubule-specific (Cdh16-cre) Kdm1A knockout mice were generated and characterized through functional assessments, biochemical techniques. The kidney response to acute injury (cisplatin) and chronic fibrosis (UUO) was evaluated in Cdh16-cre-Kdm1A knockout mice. Results: Using comprehensive multi-omics prioritization, we identified Kdm1A as a significant causal gene in kidney dysfunction. Expression analyses revealed broad kidney expression and elevated KDM1A levels in human kidney disease and animal models, suggesting a potential pathological role. Six2-cre-Kdm1A mice displayed developmental abnormalities and significant growth retardation, underscoring the essential role of KDM1A in kidney organogenesis. Interestingly, Cdh16-cre-Kdm1A mice while phenotypically normal at baseline, exhibited marked resistance to both acute kidney injury and chronic kidney fibrosis, highlighting KDM1A’s complex, context-dependent role. Molecular studies revealed reduced expression of critical genes, including HNF1a and GDNF in Six2-cre-Kdm1A mice, correlating with impaired transporter expression. Conversely, Cdh16-cre-Kdm1A mice showed elevated levels of methylated histone markers, indicating altered epigenetic states linked to injury resistance. Conclusion: Our study highlights KDM1A as a pivotal epigenetic regulator with a dual and context-specific role in kidney biology, presenting both developmental necessity and pathological potential. Further mechanistic studies are essential to fully exploit KDM1A as a target for therapeutic interventions in chronic kidney disease. Funding: NIDDK Support