Potential targeting of urokinase-type plasminogen activator receptor–formyl peptide receptor signaling to prevent recurrence in posttransplant primary podocytopathies

Abstract

Primary podocytopathies are a group of disorders characterized by nephrotic syndrome and frequent progression to kidney failure, with high rates of posttransplant recurrence. Increased expression of the urokinase-type plasminogen activator receptor (uPAR) has been associated with podocyte dysfunction in primary podocytopathies. uPAR can interact with formyl peptide receptors (FPRs) in podocytes, but the relevance of this signaling pathway in these diseases remains unclear. We retrospectively evaluated uPAR-FPR expression in renal biopsies from patients with primary podocytopathies with recurrent disease after transplantation. Upregulation of uPAR-FPR signaling was consistently observed in podocytes from kidney biopsies of patients with primary podocytopathies and in cultured podocytes exposed to sera from patients with recurrent disease. Pharmacologic inhibition of uPAR-FPR interactions with UPARANT restored podocyte plasticity, reversing cytoskeletal alterations and protecting against damage. This treatment also led to significant functional recovery in an in vitro glomerular filtration barrier model. Finally, targeting uPAR-FPR crosstalk in a zebrafish model of podocytopathy reversed podocyte foot process effacement and reduced glomerular loss of high-molecular weight dextran, effectively alleviating the disease phenotype. Our data indicate that pharmacologic targeting of the uPAR-FPR axis protects podocytes from damage and may preserve renal function in primary podocytopathies, potentially reducing recurrence after transplantation.