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 alpha v beta 3 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 alpha v beta 3 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.
Full-length soluble urokinase plasminogen activator receptor down-modulates nephrin expression in podocytes / M. Alfano, P. Cinque, G. Giusti, S. Proietti, M. Nebuloni, S. Danese, S. D'Alessio, M. Genua, F. Portale, M. Lo Porto, P.C. Singhal, M.P. Rastaldi, M.A. Saleem, D. Mavilio, J. Mikulak. - In: SCIENTIFIC REPORTS. - ISSN 2045-2322. - 5(2015 Sep), pp. 13647.1-13647.12.
|Titolo:||Full-length soluble urokinase plasminogen activator receptor down-modulates nephrin expression in podocytes|
MAVILIO, DOMENICO (Corresponding)
|Settore Scientifico Disciplinare:||Settore MED/46 - Scienze Tecniche di Medicina di Laboratorio|
Settore MED/04 - Patologia Generale
Settore MED/14 - Nefrologia
Settore MED/17 - Malattie Infettive
|Data di pubblicazione:||set-2015|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1038/srep13647|
|Appare nelle tipologie:||01 - Articolo su periodico|