Glucosylceramide regulates mitochondrial function, inflammation, and fibrosis in diabetic kidneys

Background: Altered lipid metabolism is increasingly recognized as a key mediator of renal lipid accumulation, inflammation, oxidative stress, and fibrosis. Recent studies indicate a role for ceramides and sphingolipids in the pathogenesis and progression of kidney disease in diabetes and in obesity. Glucosylceramide is a particular species of glycosphingolipid that is synthesized by the addition of sugar to ceramide by glucosylceramide synthase (Ugcg). Further glycosylation pathways result in the formation of over 300 glycosphingolipids, including lactosylceramide, GM1, and GM3. Methods: To address whether glucosylceramide plays a role in the pathogenesis of diabetic kidney disease, we used a db/db mice as a model of type 2 diabetes to examine whether glucosylceramide levels change in diabetic kidneys. To test whether the inhibition of glucosylceramide synthase could mediate the beneficial effects of reduced glucosylceramide level in the kidney, we treated diabetic mice with the FDA-approved UGCG inhibitor eliglustat. Results: Using lipidomics, we have found increased glucosylceramide levels in the kidneys of diabetic db/db mice compared to nondiabetic db/m mice. We further investigated the glucosylceramide synthase UGCG expression and regulation in the diabetic kidney. UGCG is expressed in podocytes and tubular cells of human and mouse kidney, as determined by single nuclei RNA-seq and IHC and IF. We overexpressed UGCG in mouse proximal tubule cells and found that overexpression of UGCG caused significantly increased inflammation and decreased mitochondrial gene expression and mitochondrial membrane potential. Furthermore, we found that short-term treatment of UGCG inhibitor eliglustat successfully decreased the overall glucosylceramide level in diabetic kidneys, decreased urinary albumin, and improved markers of inflammation and fibrosis. Conclusions: Our studies provide evidence to support a novel treatment avenue to use UGCG inhibitor eliglustat in the treatment and prevention of diabetic kidney disease. This work was supported by NIH (NIDDK) award numbers R01 DK139676 (ML) andR01DK127830. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.