Abstract: FR-PO0317
Donor-Specific Effects of KDM6A in Regulating Proximal Tubular Epithelial Cell Metabolism: Implications for Diabetic Kidney Disease
Session Information
- Diabetic Kidney Disease: Basic and Translational Science Advances - 1
November 07, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 701 Diabetic Kidney Disease: Basic
Authors
- Bozzo-Rey, Maya Gabrielle, McMaster University Faculty of Health Sciences, Hamilton, Ontario, Canada
- Tian, Tim, McMaster University Faculty of Health Sciences, Hamilton, Ontario, Canada
- Zorcic, Katarina, Queen's University, Kingston, Ontario, Canada
- Lin, Jonah, University of Toronto Temerty Faculty of Medicine, Toronto, Ontario, Canada
- Clotet Freixas, Sergi, McMaster University Faculty of Health Sciences, Hamilton, Ontario, Canada
Background
Diabetic kidney disease (DKD), the leading cause of chronic kidney disease, involves metabolic dysfunction in proximal tubular epithelial cells (PTECs)—the kidney’s most abundant, metabolically active cells. High glucose shifts PTECs from fatty acid oxidation to glucose and glutamine metabolism, boosting glycolytic and TCA flux and accumulating pro-inflammatory, pro-fibrotic metabolites like lactate that drive DKD. KDM6A, a histone demethylase that removes repressive epigenetic marks, is upregulated in diabetic kidneys and enhances expression of metabolic enzymes and cytokines. While its inhibition mitigates glomerular lesions in DKD mouse models, KDM6A’s role in PTEC dysfunction remains unclear. We show KDM6A mediates mitochondrial dysfunction in PTECs under high glucose, modulated by donor sex.
Methods
Primary human PTECs from different donors (Table 1) underwent 72h siRNA-mediated KDM6A inhibition, followed by 24h treatment with normal glucose (5.5 mM), high glucose (25 mM), or osmotic control (5.5 mM glucose + 19.5 mM mannitol).
Results
High glucose significantly increased extracellular lactate levels in male-derived PTECs. KDM6A knockdown reduced lactate secretion in cells of all donors. In PTECs of one male donor, KDM6A silencing also prevented high glucose-induced upregulation of LDHA and MDH2, key enzymes in glycolysis and the TCA cycle. In all donors, KDM6A inhibition elevated extracellular glucose levels, especially in the donor most sensitive to KDM6A knockdown. Additionally, KDM6A inhibition prevented increased secretion of pro-inflammatory cytokines in PTECs of both male donors under high glucose, while lowering only IL-6 in female PTECs.
Conclusion
Preliminary findings suggest that KDM6A promotes a high-glucose-induced metabolic switch in PTECs, particularly in male-derived cells. Given observed sex differences and donor-specific responses, future studies will include a broader panel of donor-derived PTECs to determine KDM6A’s role across individuals. This will clarify donor-specific effects and refine its potential as a personalized therapeutic target in DKD.
Donor Information
| Donor | Age (years) | Sex | Ethnicity/Race | BMI |
| Donor 1 | 45 years | Male | Hispanic | 31 |
| Donor 2 | 34 years | Female | Caucasian | 18 |
| Donor 3 | 31 years | Male | African American | 26 |
Funding
- Private Foundation Support