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.
Highlights
Increased plasma level of soluble urokinase-type plasminogen activator receptor was associated recently with focal segmental glomerulosclerosis (FSGS)
To both confirm the modulation of nephrin exerted by soluble uPAR (suPAR) and to disclose the related mechanism in a post-mitotic podocyte, we repeated the same experimental approach in conditional immortalized human podocytes (CIHPs) in vitro[34]
By performing assessments of protein expression with immune-flourescence in CIHPs incubated with different concentrations of suPAR for 24 hours, we detected a significant reduction of nephrin flourescence intensity and a lower level of nephrin protein in suPAR stimulated CIHPs comparing to control experiments, with the maximum inhibition between 10–20 ng/mL of suPAR (Fig. 2a)
Summary
Increased plasma level of soluble urokinase-type plasminogen activator receptor (suPAR) was associated recently with focal segmental glomerulosclerosis (FSGS). This study unveiled that interaction of full-length suPAR with αvβ[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. We demonstrated that only the full-length form, but not c-suPAR variant, is associated with the negative modulation of nephrin through a direct interaction with α vβ 3 integrin This mechanism was further supported by an in vivo model of suPAR knock out (Plaur−/−) mouse showing that the infusion of high dose of suPAR inhibits expression of nephrin and Wilms’ tumor 1 (WT-1) in podocytes and induces proteinuria indicating that the full length suPAR might actively contribute to the podocytes dysfunction in different human pathologies
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call