Kidney Week

Abstract: SA-PO708

Pharmacologic Inhibition of Urokinase-Type Plasminogen Activator Receptor (uPAR)-Formyl Peptide Receptor (FPR) Signaling Prevents Podocyte Damage in Primary Podocytopathies

Session Information

• Glomerular Diseases: Therapeutic Strategies
  October 26, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology

Authors

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

Manuel Alfredo Podestà, MD

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

Deborah Mattinzoli, PhD

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

Masami Ikehata, MD, PhD

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

Min Li, MD

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

Silvia Armelloni, PhD

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

Francesca Zanoni, MD

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

Carlo Alfieri, MD

• Messa, Piergiorgio, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Lombardia, Italy

Piergiorgio Messa

• Diana, Alberto, Universita degli Studi di Milano, Milano, Italy

Alberto Diana, PhD

• Del Giacco, Luca, Universita degli Studi di Milano, Milano, Italy

Luca Del Giacco, PhD

• Pavone, Vincenzo, Universita degli Studi di Napoli Federico II, Napoli, Campania, Italy

Vincenzo Pavone

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

Giuseppe Castellano, MD, PhD

Background

Primary podocytopathies are a group of disorders characterized by nephrotic syndrome and frequent progression to kidney failure in patients not responding to treatment, with high rates of recurrence after transplantation. Glomerular upregulation of the urokinase-type plasminogen activator receptor (uPAR) has been linked to podocyte dysfunction in these disorders. We tested the hypothesis that inhibition of uPAR signaling via the formyl peptide receptor (FPR) would ameliorate podocyte damage in primary podocytopathies.

Methods

Renal biopsies and serum from patients with recurrent primary podocytopathies were collected. Podocyte and podocyte-endothelium co-cultures to model the glomerular filtration barrier were carried out according to previously published protocols. RT-PCR and immunostaining were performed with standard methodology. Zebrafish larvae exposed to adriamycin were used as a podocytopathy in vivo model. The peptide UPARANT was used in all experiments to inhibit the uPAR-FPR crosstalk.

Results

uPAR upregulation in kidney biopsies of patients with primary podocytopathies was accompanied by increased expression of FPR2 and integrin-αvβ3 (Fig1A). The same molecules were upregulated in podocytes exposed to sera from patients with recurrent disease (Fig1B), and pharmacologic inhibition of the uPAR-FPR interaction led to normalization of this effect. uPAR-FPR crosstalk inhibition prevented podocyte damage induced by recurrent sera (Fig1C), resulting in significant functional rescue in an in-vitro model of the glomerular filtration barrier (Fig 1D). Consistently, targeting of uPAR-FPR crosstalk in a zebrafish larval model of podocytopathy led to functional (Fig1E, high-MW dextran clearance) and ultrastructural (Fig1F) rescue of the disease phenotype.

Conclusion

Pharmacologic targeting of the uPAR-FPR axis confers protection against podocyte damage and may preserve renal function in primary podocytopathies.

Funding

• Government Support – Non-U.S.