Empagliflozin reduces podocyte lipotoxicity in experimental Alport syndrome

  1. Mengyuan Ge
  2. Judith Molina
  3. Jin Ju Kim
  4. Shamroop Kumar Mallela
  5. Anis Ahmad
  6. Javier Varona Santos
  7. Hassan Al-Ali
  8. Alla Mitrofanova
  9. Kumar Sharma
  10. Flavia Fontanesi
  11. Sandra Merscher
  12. Alessia Fornoni  Is a corresponding author
  1. University of Miami, United States
  2. 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

  1. Mengyuan Ge

    Department of Medicine, University of Miami, Miami, United States
    Competing interests
    No competing interests declared.
  2. Judith Molina

    Department of Medicine, University of Miami, Miami, United States
    Competing interests
    No competing interests declared.
  3. Jin Ju Kim

    Department of Medicine, University of Miami, Miami, United States
    Competing interests
    No competing interests declared.
  4. Shamroop Kumar Mallela

    Department of Medicine, University of Miami, Miami, United States
    Competing interests
    No competing interests declared.
  5. Anis Ahmad

    Department of Radiation Oncology, University of Miami, Miami, United States
    Competing interests
    No competing interests declared.
  6. Javier Varona Santos

    Department of Medicine, University of Miami, Miami, United States
    Competing interests
    No competing interests declared.
  7. Hassan Al-Ali

    Department of Medicine, University of Miami, Miami, United States
    Competing interests
    No competing interests declared.
  8. Alla Mitrofanova

    Department of Medicine, University of Miami, Miami, United States
    Competing interests
    No competing interests declared.
  9. Kumar Sharma

    Center for Precision Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, United States
    Competing interests
    Kumar Sharma, is founder of SygnaMap..
  10. Flavia Fontanesi

    Department of Biochemistry and Molecular Biology, University of Miami, Miami, United States
    Competing interests
    No competing interests declared.
  11. Sandra Merscher

    Department of Medicine, University of Miami, Miami, United States
    Competing interests
    Sandra Merscher, is an inventor on pending (PCT/US2019/032215; US 17/057,247; PCT/US2019/041730; PCT/US2013/036484; US 17/259,883; US17/259,883; JP501309/2021, EU19834217.2; CN-201980060078.3; CA2,930,119; CA3,012,773,CA2,852,904) or issued patents (US10,183,038 and US10,052,345) aimed at preventing and treating renal disease. They stand to gain royalties from their future commercialization. SM holds indirect equity interest in, and potential royalty from, ZyVersa Therapeutics, Inc. by virtue of assignment and licensure of a patent estate. SM is supported by Aurinia Pharmaceuticals Inc..
  12. Alessia Fornoni

    Department of Biochemistry and Molecular Biology, University of Miami, Miami, United States
    For correspondence
    AFornoni@med.miami.edu
    Competing interests
    Alessia Fornoni, is an inventor on pending (PCT/US2019/032215; US 17/057,247; PCT/US2019/041730; PCT/US2013/036484; US 17/259,883; US17/259,883; JP501309/2021, EU19834217.2; CN-201980060078.3; CA2,930,119; CA3,012,773,CA2,852,904) or issued patents (US10,183,038 and US10,052,345) aimed at preventing and treating renal disease. They stand to gain royalties from their future commercialization. AF is Vice-President of L&F Health LLC and is a consultant for ZyVersa Therapeutics, Inc. ZyVersa Therapeutics, Inc has licensed worldwide rights to develop and commercialize hydroxypropyl-beta-cyclodextrin from L&F Research for the treatment of kidney disease. AF also holds equities in Renal 3 River Corporation. AF and SM are supported by Aurinia Pharmaceuticals Inc..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1313-7773

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.

Reviewing Editor

  1. Ilse S Daehn, Icahn School of Medicine at Mount Sinai, United States

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.

Version history

  1. Received: September 8, 2022
  2. Preprint posted: October 4, 2022 (view preprint)
  3. Accepted: April 26, 2023
  4. Accepted Manuscript published: May 2, 2023 (version 1)
  5. 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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  1. Mengyuan Ge
  2. Judith Molina
  3. Jin Ju Kim
  4. Shamroop Kumar Mallela
  5. Anis Ahmad
  6. Javier Varona Santos
  7. Hassan Al-Ali
  8. Alla Mitrofanova
  9. Kumar Sharma
  10. Flavia Fontanesi
  11. Sandra Merscher
  12. Alessia Fornoni
(2023)
Empagliflozin reduces podocyte lipotoxicity in experimental Alport syndrome
eLife 12:e83353.
https://doi.org/10.7554/eLife.83353

Share this article

https://doi.org/10.7554/eLife.83353

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