Abstract: FR-PO323
Empagliflozin Reduces Renal Lipotoxicity in Alport Syndrome
Session Information
- Genetic Diseases: Models, Mechanisms, Treatments
November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1102 Genetic Diseases of the Kidneys: Non-Cystic
Authors
- Ge, Mengyuan, University of Miami School of Medicine, Miami, Florida, United States
- Molina David, Judith T., University of Miami School of Medicine, Miami, Florida, United States
- Kim, Jin Ju, University of Miami School of Medicine, Miami, Florida, United States
- Varona Santos, Javier T., University of Miami School of Medicine, Miami, Florida, United States
- Fontanesi, Flavia, University of Miami School of Medicine, Miami, Florida, United States
- Merscher, Sandra M., University of Miami School of Medicine, Miami, Florida, United States
- Fornoni, Alessia, University of Miami School of Medicine, Miami, Florida, United States
Background
Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are antidiabetic drugs that prevent glucose reabsorption in proximal tubular cells. SGLT2i improves renal outcomes in both diabetic and non-diabetic patients, indicating it may have beneficial effects beyond glycemic control. Alport Syndrome (AS) is a genetic disorder that leads to progressive kidney disease. We and others have shown that lipid accumulation in podocytes and tubular cells contributes to the pathogenesis of AS. Tubular cells preferentially use fatty acids as the main energy source, while podocytes rely on glucose. With this study, we test the hypothesis that SGLT2i affects energy metabolism in podocytes and tubular cells in experimental AS.
Methods
SGLT2 expression was analyzed by Western blot. Lipid droplet (LD) accumulation was determined by Nile red staining. Respiration was measured using Oroboros O2k respirometer. Blood samples were studied for BUN and creatinine levels. Albumin-to-creatinine ratios (ACR) were determined by albumin ELISA and creatinine assay. Kidney cortices were collected for lipid content analysis using Amplex Red assay and triglyceride (TG) assay.
Results
In vitro, we demonstrated a similar level of SGLT2 protein expression in cultured human and mouse podocytes when compared to tubular cells. Newly established immortalized podocytes from Col4a3KO mice (AS) accumulate LDs in association with increased apoptosis when compared to wildtype (WT) podocytes. Treatment with empagliflozin (empa, SGLT2i) reduces LD accumulation and apoptosis in AS podocytes. Empa inhibits the utilization of glucose as a metabolic substrate in AS podocytes. Interestingly, empa did not affect LD content and glucose utilization in tubular cells isolated from AS mice when compared to WT. In vivo, we demonstrated that empa reduces ACR and prolongs the survival of AS mice. Empa-treated AS mice showed decreased serum BUN and creatinine levels in association with reduced TGs and cholesterol esters (CE) levels in the kidney cortices when compared to AS mice. Lipid accumulation (TG, CE) in kidney cortices correlated with the decline in renal function (ACR, serum BUN and creatinine).
Conclusion
Empa reduces renal lipotoxicity and improves kidney function in experimental AS in association with a shift in the use of energy substrates from glucose to fatty acids in podocytes.
Funding
- NIDDK Support