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

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 patholog...

Full description

Saved in:
Bibliographic Details
Published in:Scientific reports 2015-09, Vol.5 (1), p.13647-13647, Article 13647
Main Authors: 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
Format: Article
Language:English
Subjects:
Animals
Diabetes mellitus
Down-Regulation
Gene Expression Regulation
Genetic Variation
Hantavirus
Humans
Integrin alphaVbeta3 - metabolism
Kidneys
Membrane Proteins - genetics
Membrane Proteins - metabolism
Mice
Mice, Knockout
Podocytes - metabolism
Promoter Regions, Genetic
Protein Binding
Proteinuria
Proteinuria - genetics
Proteinuria - metabolism
Receptors, Urokinase Plasminogen Activator - blood
Receptors, Urokinase Plasminogen Activator - genetics
Receptors, Urokinase Plasminogen Activator - metabolism
Rodents
U-Plasminogen activator
Wilms' tumor
WT1 Proteins
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:2045-2322
2045-2322
DOI:10.1038/srep13647