Abstract: SA-PO0315
CerS6 and C16 Ceramide in Early-Stage Diabetic Kidney Disease: Potential Role of Adenine in Podocytopathy
Session Information
- Diabetic Kidney Disease: Basic and Translational Science Advances - 2
November 08, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 701 Diabetic Kidney Disease: Basic
Authors
- Zhang, Guanshi, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
- Lee, Hak Joo, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
- Zhao, Qingwei, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
- Ragi, Nagarjunachary, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
- Feng, Tianqing, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
- Trevino, Esmeralda, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
- Montellano, Richard, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
- Zhang, Shiqi, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
- Sharma, Kumar, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
Background
In diabetic kidney disease (DKD), identifying key biomarkers and pathways is essential for improving patient outcomes. Recent studies highlight endogenous adenine as a mediator of kidney injury, with elevated urine adenine/creatinine ratios strongly linked to end-stage kidney disease and mortality. Adenine’s profibrotic effects, driven via the mTOR pathway, emphasize its role in kidney pathology. Concurrently, ceramide synthase 6 (CerS6) upregulation in podocytes contributes to lipid dysregulation, podocyte injury, glomerulosclerosis, and proteinuria. The convergence of adenine and CerS6 pathways on cellular stress and fibrosis suggests potential synergistic mechanisms in DKD progression, meriting further investigation into their roles in podocyte dysfunction and kidney injury.
Methods
Wild-type (WT) C57BL/6J mice received adenine-supplemented or control water for 4 weeks. Male db/db mice, modeling early-stage DKD, and age-matched db/m heterozygous controls were administered methylthioadenosine phosphorylase (MTAP) inhibitor (MTDIA) or vehicle via drinking water for 8 weeks. Kidney tissues were analyzed using immunofluorescence, western blotting, and bulk lipidomics. Plasma ceramide levels were measured. In vitro studies utilized human and rat podocytes.
Results
Adenine exposure increased CerS6 expression and C16 ceramide (Cer) in WT mouse renal cortex and rat podocytes. In db/db mice, podocyte CerS6 expression and renal cortical C16 ceramide (Cer) levels were elevated when compared to db/m mice, and C16:0 Cer concentration was reduced by MTAP inhibition. Plasma C16 Cer levels positively correlated with kidney cortex concentrations in db/db mice, suggesting C16 Cer as a non-invasive biomarker for early DKD. High glucose (HG) increased C16 Cer production at 24 and 48 hours and induced apoptosis at 48 hours: these effects were reduced by MTAP inhibition in human podocytes.
Conclusion
CerS6 upregulation and C16 Cer accumulation are key features of early-stage DKD, with plasma C16 ceramide showing potential as a non-invasive biomarker. Adenine may play a key role in podocyte apoptosis and MTAP inhibition can reduce C16 Cer-mediated podocyte injury and/or apoptosis in DKD.
Funding
- NIDDK Support