Abstract: TH-PO0701
SGLT2 Inhibitor Reverts Podocyte Senescence by Inhibiting Cell-Autonomous Complement Activation
Session Information
- Glomerular Diseases: Immunopathogenesis and Targeted Therapeutics
November 06, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Castellano, Giuseppe, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Lombardy, Italy
- Li, Min, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Lombardy, Italy
- Stravalaci, Matteo, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Lombardy, Italy
- Mattinzoli, Deborah, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Lombardy, Italy
- Armelloni, Silvia, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Lombardy, Italy
- Ikehata, Masami, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Lombardy, Italy
- Alfieri, Carlo, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Lombardy, Italy
- Colombo, Federico Simone, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Lombardy, Italy
- Trombetta, Elena, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Lombardy, Italy
- Zanoni, Francesca, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Lombardy, Italy
- Lambris, John, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States
- Podestà, Manuel Alfredo, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Lombardy, Italy
Background
Complement deposition is a hallmark of several glomerulonephritis, which correlates with worse prognosis. Podocytes (PODOs) are specialized epithelial cells responsible of the integrity of the glomerular filtration barrier. Dysregulation of the complement system may play a key role in to podocyte senescence, an important driver of chronic kidney disease (CKD) progression and glomerulosclerosis. Recent studies have shown that sodium-glucose co-transporter 2 inhibitors (SGLT2i) provide renal and cardiovascular protection regardless of hypoglicaemia. However, the mechanisms underlying kidney protection remain not fully understood. In this study we investigated if SGLT2i could have a direct effect on podocyte senescence through modulation of the complement system.
Methods
Senescence of PODOs was induced by Adryamicin (ADR)-mediated cell injury. Cells were treated with ADR alone or in combination with Dapagliflozin (Dapa), Cp40 (a C3 convertase inhibitor), or a C3a receptor antagonist (C3aRA). In some experiments, PODOs were treated with recombinant IL-1β, alone or in combination with either C3aRA or Dapa. The expression of podocyte markers, complement components, and activated Caspase-3 (a marker of cell apoptosis) were assessed using immunofluorescence, Western blotting, qPCR, and flow cytometry
Results
PODOs constitutively expresses both soluble and membrane-bound complement proteins, including C3 and FB. Treatment with ADR induced the activation of the complement system by increased expression of C3a. Cp40-mediated complement inhibition, or pharmacological blockade of C3aR, reversed ADR-induced damage on podocytes, as demonstrated by increased Nephrin expression and Actin reorganization, along with a decrease in apoptosis. Notably, in ADR-treated podocyte, we found an intracellular expression of Bb, a product of the AP, which was reduced by administration of either Dapa or Cp40. IL-1β, part of the SASP, induced podocyte injury, which could be prevented by C3aR blockade or Dapa
Conclusion
Overall, these data suggests that cell-autonomous complement activation may contribute to podocyte senescence. SGLT2i acted as potent senomorphing drug on podocytes, by inhibiting complement-mediated inflammation and reversing cell senescence.
Funding
- Government Support – Non-U.S.