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Sci Rep ; 5: 13647, 2015 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-26380915

RESUMO

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 αvß3 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 αvß3 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.


Assuntos
Regulação da Expressão Gênica , Proteínas de Membrana/genética , Podócitos/metabolismo , Receptores de Ativador de Plasminogênio Tipo Uroquinase/metabolismo , Animais , Regulação para Baixo , Variação Genética , Humanos , Integrina alfaVbeta3/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout , Regiões Promotoras Genéticas , Ligação Proteica , Proteinúria/genética , Proteinúria/metabolismo , Receptores de Ativador de Plasminogênio Tipo Uroquinase/sangue , Receptores de Ativador de Plasminogênio Tipo Uroquinase/genética , Proteínas WT1
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