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Empagliflozin reduces podocyte lipotoxicity in experimental Alport syndrome
Mengyuan Ge1,2, Judith Molina1,2, Jin-Ju Kim1,2
1Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, United States.
Abstract:
Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are anti-hyperglycemic agents 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. Here, we demonstrate that SGLT2i affects energy metabolism and podocyte lipotoxicity in experimental Alport syndrome (AS). In vitro, we found that the SGLT2 protein was expressed in human and mouse podocytes to a similar extent in tubular cells. Newly established immortalized podocytes from Col4a3 knockout mice (AS podocytes) accumulate lipid droplets along with increased apoptosis when compared to wild-type podocytes. Treatment with SGLT2i empagliflozin reduces lipid droplet accumulation and apoptosis in AS podocytes. Empagliflozin inhibits the utilization of glucose/pyruvate as a metabolic substrate in AS podocytes but not in AS tubular cells. In vivo, we demonstrate that empagliflozin reduces albuminuria and prolongs the survival of AS mice. Empagliflozin-treated AS mice show decreased serum blood urea nitrogen and creatinine levels in association with reduced triglyceride and cholesterol ester content in kidney cortices when compared to AS mice. Lipid accumulation in kidney cortices correlates with a decline in renal function. In summary, empagliflozin reduces podocyte lipotoxicity and improves kidney function in experimental AS in association with the energy substrates switch from glucose to fatty acids in podocytes.
Insights
Sodium-glucose cotransporter-2 inhibitors (SGLT2i) improve kidney function in Alport syndrome by reducing podocyte lipotoxicity. This class of drugs shifts podocyte energy metabolism from glucose to fatty acids, enhancing renal outcomes.
Area of Science:
- Nephrology
- Metabolic Research
- Pharmacology
Background:
- Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are known for glycemic control but show renal benefits beyond diabetes.
- Alport syndrome (AS) is a genetic kidney disease characterized by progressive renal damage.
- Podocyte injury and lipotoxicity are key contributors to AS progression.
Purpose of the Study:
- To investigate the effects of SGLT2 inhibitors on energy metabolism and podocyte lipotoxicity in experimental Alport syndrome.
- To determine if SGLT2 inhibition can ameliorate kidney dysfunction and improve outcomes in AS.
Main Methods:
- In vitro studies using immortalized podocytes and tubular cells from Col4a3 knockout (AS) mice and wild-type controls.
- In vivo studies using empagliflozin treatment in experimental Alport syndrome mouse models.
- Assessment of lipid droplet accumulation, apoptosis, albuminuria, serum creatinine, blood urea nitrogen, and kidney lipid content.
Main Results:
- SGLT2 protein is expressed in both podocytes and tubular cells.
- Empagliflozin treatment reduced lipid droplet accumulation and apoptosis in AS podocytes.
- In AS mice, empagliflozin decreased albuminuria, prolonged survival, and reduced kidney lipid content, correlating with improved renal function.
- Empagliflozin shifted AS podocyte metabolism away from glucose/pyruvate utilization.
Conclusions:
- SGLT2 inhibitors, like empagliflozin, can reduce podocyte lipotoxicity and improve kidney function in experimental Alport syndrome.
- The beneficial effects are associated with a metabolic shift in podocytes from glucose to fatty acid utilization.
- SGLT2 inhibitors may represent a therapeutic strategy for Alport syndrome, independent of glycemic control.
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