Full-length soluble urokinase plasminogen activator receptor down-modulates nephrin expression in podocytes

Massimo Alfano, Paola Cinque, Guido Giusti, Silvia Proietti, Manuela Nebuloni, Silvio Danese, Silvia D'Alessio, Marco Genua, Federica Portale, Manuela Lo Porto, Pravin C. Singhal, Maria Pia Rastaldi, Moin A. Saleem, Domenico Mavilio, Joanna Mikulak

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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.

Original languageEnglish
Article number13647
JournalScientific Reports
Volume5
DOIs
Publication statusPublished - Sep 18 2015

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Urokinase Plasminogen Activator Receptors
Podocytes
Wilms Tumor
Integrins
Hantavirus Infections
Pathology
Focal Segmental Glomerulosclerosis
nephrin
Nephrotic Syndrome
Proteinuria
Knockout Mice
HIV Infections
Transcription Factors
Kidney

ASJC Scopus subject areas

  • General

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Full-length soluble urokinase plasminogen activator receptor down-modulates nephrin expression in podocytes. / Alfano, Massimo; Cinque, Paola; Giusti, Guido; Proietti, Silvia; Nebuloni, Manuela; Danese, Silvio; D'Alessio, Silvia; Genua, Marco; Portale, Federica; Lo Porto, Manuela; Singhal, Pravin C.; Rastaldi, Maria Pia; Saleem, Moin A.; Mavilio, Domenico; Mikulak, Joanna.

In: Scientific Reports, Vol. 5, 13647, 18.09.2015.

Research output: Contribution to journalArticle

Alfano, Massimo ; Cinque, Paola ; Giusti, Guido ; Proietti, Silvia ; Nebuloni, Manuela ; Danese, Silvio ; D'Alessio, Silvia ; Genua, Marco ; Portale, Federica ; Lo Porto, Manuela ; Singhal, Pravin C. ; Rastaldi, Maria Pia ; Saleem, Moin A. ; Mavilio, Domenico ; Mikulak, Joanna. / Full-length soluble urokinase plasminogen activator receptor down-modulates nephrin expression in podocytes. In: Scientific Reports. 2015 ; Vol. 5.
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