title: Full-length soluble urokinase plasminogen activator receptor down-modulates nephrin expression in podocytes.
abstract: Increased plasma level of soluble urokinase-type plasminogen activator receptor (suPAR) was associated recently with focal segmental glomerulosclerosis (FSGS). In addition, different clinical studies observed increased concentration of suPAR in various glomerular diseases and in other human pathologies with nephrotic syndromes such as HIV and Hantavirus infection, diabetes and cardiovascular disorders. Here, we show that suPAR induces nephrin down-modulation in human podocytes. This phenomenon is mediated only by full-length suPAR, is time-and dose-dependent and is associated with the suppression of Wilms' tumor 1 (WT-1) transcription factor expression. Moreover, an antagonist of αvβ3 integrin RGDfv blocked suPAR-induced suppression of nephrin. These in vitro data were confirmed in an in vivo uPAR knock out Plaur(-/-) mice model by demonstrating that the infusion of suPAR inhibits expression of nephrin and WT-1 in podocytes and induces proteinuria. This study unveiled that interaction of full-length suPAR with αvβ3 integrin expressed on podocytes results in down-modulation of nephrin that may affect kidney functionality in different human pathologies characterized by increased concentration of suPAR.
authors.affiliation: Division of Oncology, Urological Research Institute URI; IRCCS Ospedale San Raffaele, Milan, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Alfano
authors.affiliation: Department of Infectious Diseases, IRCCS Ospedale San Raffaele, Milan, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Cinque
authors.affiliation: Depatment of Urology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
authors.forename: Guido
authors.initials: G
authors.lastname: Giusti
authors.affiliation: Depatment of Urology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Proietti
authors.affiliation: Pathology Unit, L. Sacco Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Nebuloni
authors.affiliation: IBD Center, Humanitas Clinical and Research Center, Rozzano, Italy.
authors.forename: Silvio
authors.initials: S
authors.lastname: Danese
authors.affiliation: IBD Center, Humanitas Clinical and Research Center, Rozzano, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: D'Alessio
authors.affiliation: IBD Center, Humanitas Clinical and Research Center, Rozzano, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Genua
authors.affiliation: Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Portale
authors.affiliation: Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Lo Porto
authors.affiliation: Center for Excellence for Immunology and Inflammation, Feinstein Institute for Medical Research, Hofstra North Shore Long Island Jewish Medical School, New Hyde Park, NY, USA.
authors.forename: Pravin C
authors.initials: PC
authors.lastname: Singhal
authors.affiliation: Renal Research Laboratory, Fondazione IRCCS Ospedale Maggiore Policlinico and Fondazione D'Amico per la Ricerca sulle Malattie Renali, Milan, Italy.
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Rastaldi
authors.affiliation: Children's Renal Unit and Academic Renal Unit, University of Bristol, Bristol, United Kingdom.
authors.forename: Moin A
authors.initials: MA
authors.lastname: Saleem
authors.affiliation: Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.|Department of Medical Biotechnologies and Translational Medicine (BioMeTra), University of Milan, Milan, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Mavilio
authors.affiliation: Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
authors.forename: Joanna
authors.initials: J
authors.lastname: Mikulak
mesh_terms: D000818:Animals; D015536:Down-Regulation; D005786:Gene Expression Regulation; D014644:Genetic Variation; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D050199:Podocytes / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011507:Proteinuria / Q000235:genetics / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D025721:WT1 Proteins
chemical_list: D039302:Integrin alphaVbeta3; D008565:Membrane Proteins; D055293:Receptors, Urokinase Plasminogen Activator; D025721:WT1 Proteins; C113267:nephrin