Abstract: TH-PO1178
Context-Dependent Role of Lysine-Specific Demethylase 1A in Kidney Development and Diseases
Session Information
- CKD: Mechanisms, AKI, and Beyond - 1
November 06, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2303 CKD (Non-Dialysis): Mechanisms
Authors
- Prasanna, Kolligundla Lakshmi, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States
- Mukhi, Dhanunjay, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States
- Susztak, Katalin, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States
Group or Team Name
- Katalin Susztak's Group.
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