Abstract: FR-PO0193
Targeting Glucosylceramide Synthesis Improves Kidney Injury in Diabetic Kidney Disease
Session Information
- Diabetic Kidney Disease: Metabolic, Mitochondrial, and Inflammatory Mechanisms
October 23, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Cardiovascular-Kidney-Metabolic Health
- 601 Cardiovascular-Kidney-Metabolic Health: Basic
Authors
- Wang, Xiaoxin, Georgetown University, Washington, District of Columbia, United States
- Myakala, Komuraiah, Georgetown University, Washington, District of Columbia, United States
- Krawczyk, Ewa, Georgetown University, Washington, District of Columbia, United States
- Cowart, Lauren A., Virginia Commonwealth University, Richmond, Virginia, United States
- Rosenberg, Avi Z., Johns Hopkins University, Baltimore, Maryland, United States
- Glunde, Kristine, Johns Hopkins University, Baltimore, Maryland, United States
- Levi, Moshe, Georgetown University, Washington, District of Columbia, United States
Background
Altered lipid metabolism is increasingly recognized as key mediators of renal lipid accumulation, inflammation, oxidative stress, and fibrosis. Glucosylceramide synthase which mediates glucosylceramide synthesis is expressed in human podocytes and tubular cells, and in mouse podocytes, and proximal tubular cells. We found that using LC-MS glucosylceramide levels are increased in the kidneys of diabetic db-db mice. MALDI imaging further documented increases in glucosylceramide and lactosylceramide in the glomeruli and tubules of db-db mice.
Methods
To determine a role for glucosylceramide in diabetic kidney disease we treated diabetic mice with Eliglustat, an inhibitor of glucosylceramide synthase. To further determine a role for glucosylceramide we overexpressed UGCG (glucosylceramide synthase) in mouse proximal tubule cells.
Results
In mice treated with Eliglustat, we found that the decrease in glucosylceramide levels were associated with a significant decrease in albuminuria, increase in nephrin expression, and decreases in fibronectin and collagen IV. There was also a decrease in CD45 expression. In cells with UGCG overexpression, we found this resulted in significant increases in TNF alpha and MCP-1, whereas there were significant decreases in mitochondrial membrane potential, PGC-1a, an important mediator of mitochondrial biogenesis, and Cpt1a, a mediator of mitochondrial fatty acid oxidation.
Conclusion
Our results therefore indicate an important role for glucosylceramide in the pathogenesis of diabetic kidney disease.
Acknowledgment
NIH R01 grant DK139676
Funding
- NIDDK Support