Kidney Week

Abstract: TH-PO0432

Cell Autonomous Complement Activation Drives Senescence in Human Podocytes

Session Information

• Glomerular Diseases: Autoimmune Diseases
  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, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Lombardy, Italy

Giuseppe Castellano, MD, PhD

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

Min Li, MD

• Margeri, Dario, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Lombardy, Italy

Dario Margeri, MSc

• Inanloo Nigi Jak, Farzaneh, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Lombardy, Italy

Farzaneh Inanloo Nigi Jak

• Di Naro, Margherita, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Lombardy, Italy

Margherita Di Naro, MD

• Lonati, Caterina, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Lombardy, Italy

Caterina Lonati, PhD

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

Carlo Alfieri, MD

• Zanoni, Francesca, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Lombardy, Italy

Francesca Zanoni, MD

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

Manuel Alfredo Podestà, MD

• Lambris, John, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States

John Lambris, PhD

• Stravalaci, Matteo, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Lombardy, Italy

Matteo Stravalaci, PhD

Background

Complement deposition is a hallmark of glomerulonephritis, a heterogeneous group of kidney disorders characterized by inflammation and glomerular injury. Podocytes, highly specialized epithelial cells, are essential for maintaining the integrity of the glomerular filtration barrier. Dysregulated complement activation drives persistent local inflammation and may promote podocyte senescence, a key contributor to chronic kidney disease (CKD) progression and renal failure. Podocytes express multiple components of the innate immune system, including complement proteins such as C3 and Factor B. However, the extent to which cell intrinsic complement activation contributes to glomerular damage remains unclear. In this study, we investigated whether podocyte autonomous complement activation directly contributes to podocyte injury.

Methods

Human immortalized podocytes were treated with Adriamycin (ADR) alone or in combination with Dapaglifozin (a SGLT2 inhibitor), Cp40 (a C3 convertase inhibitor), a C3a receptor antagonist (C3aRA), or Iptacopan (a Factor B inhibitor) for 24 hours. All experiments were performed in serum free medium. To model podocyte senescence, cells were washed after 24 hours of ADR exposure and incubated for an additional 48 hours. The expression of podocyte senescence markers, complement components, and activated Caspase 3 (a marker of apoptosis) was assessed by a multidisciplinary approach.

Results

Adriamycin (ADR) treatment upregulated the alternative complement pathway, evidenced by increased Factor B mRNA expression. Pharmacological inhibition of complement activation with Cp40 or Iptacopan reversed ADR induced podocyte senescence, as shown by reduced phospho p53 and p21 expression, restoration of actin organization, and decreased apoptosis. Notably, ADR treated podocytes exhibited cell intrinsic C3 cleavage and production of Bb fragment, both of which were diminished by Dapagliflozin or Cp40.

Conclusion

The rapid expansion of novel therapeutics, including complement targeting agents, is reshaping the treatment landscape for glomerular kidney diseases. Our findings show that podocyte intrinsic complement activation drives ADR induced senescence and injury, identifying this pathway as a promising therapeutic target in glomerular pathology.