Empagliflozin reduces podocyte lipotoxicity in experimental Alport syndrome
- University of Miami, United States
- The University of Texas Health Science Center at San Antonio, 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 SGLT2 protein was expressed in human and mouse podocytes to a similar extent of tubular cells. Newly established immortalized podocytes from Col4a3 knockout mice (AS podocytes) accumulate lipid droplets along with increased apoptosis when compared to wildtype 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 the 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.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting file.
Article and author information
Author details
Funding
National Institutes of Health (R01DK117599,R01DK104753,R01CA227493)
- Sandra Merscher
- Alessia Fornoni
Miami Clinical and Translational Science Institute, University of Miami (U54DK083912,UM1DK100846,U01DK116101,UL1TR000460)
- Alessia Fornoni
Army Research Office (W911NF-21-1-0359)
- Flavia Fontanesi
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All studies involving mice were approved by the Institutional Animal Care and Use Committee (IACUC) at the University of Miami. The University of Miami (UM) has an Animal Welfare Assurance on file with the Office of Laboratory Animal Welfare, NIH (A-3224-01, effective November 24, 2015). Additionally, UM is registered with the US Department of Agriculture Animal and Plant Health Inspection Service, effective December 2014, registration 58-R-007. As of October 22, 2013, the Council on Accreditation of the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC International) has continued UM's full accreditation.
Reviewing Editor
- Ilse S Daehn, Icahn School of Medicine at Mount Sinai, United States
Version history
- Received: September 8, 2022
- Preprint posted: October 4, 2022 (view preprint)
- Accepted: April 26, 2023
- Accepted Manuscript published: May 2, 2023 (version 1)
- Version of Record published: May 15, 2023 (version 2)
Copyright
© 2023, Ge et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Empagliflozin reduces podocyte lipotoxicity in experimental Alport syndrome
eLife 12:e83353.
https://doi.org/10.7554/eLife.83353
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