Abstract: FR-PO1196
Lysine-Specific Demethylase 1A Is a Targetable Kidney Disease Causal Gene
Session Information
- CKD: Mechanisms - 2
October 25, 2024 | 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, Philadelphia, Pennsylvania, United States
- Mukhi, Dhanunjay, University of Pennsylvania, Philadelphia, Pennsylvania, United States
- Liu, Hongbo, University of Pennsylvania, Philadelphia, Pennsylvania, United States
- Susztak, Katalin, University of Pennsylvania, Philadelphia, Pennsylvania, United States
Group or Team Name
- Katalin Susztak Group.
Background
Large scale chronic kidney disease genome-wide association study (GWAS) identified more than eight hundred genetic risk loci for kidney dysfunction, however, causal genes, cell types, and targetable pathways remain elusive. In our research, we leveraged human kidney expression and methylation quantitative trait loci (eQTL, meQTL), and single cell open chromatin and gene expression information to prioritized KDM1A (Lysine specific demethylase 1A) on chromosome 1 as a likely causal gene. KDM1A controls genes expression by demethylating histone 3 lysine 4 di-or mono methylation residues.
Methods
We generated kidney-specific KDM1A knockout mice by breeding with KDM1A floxed mice with Six2 cre or Ksp cre mice. We analysed these mice at baseline and following kidney injury by cisplatin or unilateral ureteral obstruction. Kidney function was analyzed by measuring serum creatinine, and blood urea nitrogen, and cystatin C levels, and gene expression by real-time PCR and protein levels by western blotting, and immunohistochemistry. In addition, primary tubule cells were employed and treated with TGFβ1 or ORY-1001, an inhibitor of KDM1A, and analyzed fibrosis markers. Chromatin immunoprecipitation sequencing, single nuclear RNA-seq, and ATAC-seq were applied to find the molecular mechanism.
Results
By applying a comprehensive gene prioritization strategy, we identified that genetic variants on chromosome 1 regulate KDM1A gene expression. RNA and protein expression studies revealed that KDM1A levels were higher in kidney disease patients and animal models. Tubule-specific KDM1A knockout mice were healthy at baseline but showed lower kidney injury in models of acute kidney injury by cisplatin, and chronic fibrosis by UUO. In vitro studies with TGFβ1 treatment showed lower fibrosis markers expression in the presence of ORY-1001 or in KDM1A knockout tubule cells. Inhibition of KDM1A with ORY-1001 in mice also showed protection against UUO-induced kidney fibrosis. Our future studies will investigate the mechanistic role of KDM1A in kidney disease development.
Conclusion
Our studies propose that lysine specific demethylase 1A could be a therapeutic option to combat kidney disease.
Funding
- NIDDK Support