Kidney Week

Abstract: TH-PO0374

Reprogramming Podocyte (PODO) Senescence Through SGLT2 Inhibition in Diabetic Nephropathy (DN)

Session Information

• Glomerular Diseases: Genetics to Therapeutics
  October 22, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology

Authors

• Castellano, Giuseppe, Universita degli Studi di Milano, Milan, Lombardy, Italy

Giuseppe Castellano, MD, PhD

• Li, Min, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Lombardy, Italy

Min Li, MD

• Mattinzoli, Deborah, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Lombardy, Italy

Deborah Mattinzoli, PhD

• Armelloni, Silvia, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Lombardy, Italy

Silvia Armelloni, PhD

• Ikehata, Masami, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Lombardy, Italy

Masami Ikehata, MD, PhD

• Alfieri, Carlo, Universita degli Studi di Milano, Milan, Lombardy, Italy

Carlo Alfieri, MD

• Conserva, Francesca, Universita degli Studi di Bari Aldo Moro, Bari, Apulia, Italy

Francesca Conserva, PhD

• Pontrelli, Paola, Universita degli Studi di Bari Aldo Moro, Bari, Apulia, Italy

Paola Pontrelli, PhD

• Gesualdo, Loreto, Universita degli Studi di Bari Aldo Moro, Bari, Apulia, Italy

Loreto Gesualdo, MD

• Podestà, Manuel Alfredo, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Lombardy, Italy

Manuel Alfredo Podestà, MD

Background

SGLT2i exert nephroprotective effects beyond glucose lowering, reducing proteinuria and slowing CKD progression through mechanisms that remain incompletely understood. PODO senescence is increasingly recognized as a key driver of glomerular filtration barrier (GFB) dysfunction in proteinuric kidney diseases, including DN. We investigated whether dapagliflozin (DAPA) directly modulates senescence-associated pathways in injured PODO and explored tissue-level effects in human DN through high-dimensional spatial proteomics.

Methods

Human PODO and glomerular endothelial cells (GenCs) were used. PODO injury was induced with adriamycin (ADR), followed by treatment with DAPA (100 nM). GFB function was assessed by albumin permeability in a GenC/PODO co-culture system. Gene and protein expression were evaluated by immunofluorescence, Western blot, qPCR and ELISA. SA-βGAL activity was quantified using a dedicated assay. Renal biopsies from subjects with DN receiving DAPA therapy were analyzed using the MACSima Imaging System to characterize spatial changes in senescence, inflammatory and oxidative stress pathways within glomerular compartments.

Results

DAPA promoted recovery from ADR-induced PODO injury, restoring F-actin cytoskeletal organization by increasing nephrin and synaptopodin expression; structural changes were associated with improved GFB integrity reducing albumin permeability. At molecular level, DAPA exerted marked senomorphic effects by inhibiting p53 phosphorylation and nuclear translocation, reducing p21 expression and lowering SA-βGAL activity. Inflammatory mediators (IL-1β, IL-6 and IL-8) were significantly downregulated at both transcriptional and protein levels. Spatial proteomic analysis of human DN tissue revealed reduced glomerular senescence and inflammatory signaling after 3 months of SGLT2i exposure, including decreased phospho-p53, MCP1 and TGFβ1 expression, restoration of nephrin expression, and increased expression of the anti-oxidative stress marker SOD2.

Conclusion

DAPA exerts direct senomorphic and anti-inflammatory effects on injured PODO, promoting structural and functional recovery of the glomerular filtration barrier. These findings identify modulation of cellular senescence as a potential mechanism underlying SGLT2i nephroprotection and provide spatially resolved evidence supporting tissue-level reprogramming of inflammatory and senescence pathways in DN.

Acknowledgment

None