Document Detail


Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis.
MedLine Citation:
PMID:  21804539     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Focal segmental glomerulosclerosis (FSGS) is a cause of proteinuric kidney disease, compromising both native and transplanted kidneys. Treatment is limited because of a complex pathogenesis, including unknown serum factors. Here we report that serum soluble urokinase receptor (suPAR) is elevated in two-thirds of subjects with primary FSGS, but not in people with other glomerular diseases. We further find that a higher concentration of suPAR before transplantation underlies an increased risk for recurrence of FSGS after transplantation. Using three mouse models, we explore the effects of suPAR on kidney function and morphology. We show that circulating suPAR activates podocyte β(3) integrin in both native and grafted kidneys, causing foot process effacement, proteinuria and FSGS-like glomerulopathy. Our findings suggest that the renal disease only develops when suPAR sufficiently activates podocyte β(3) integrin. Thus, the disease can be abrogated by lowering serum suPAR concentrations through plasmapheresis, or by interfering with the suPAR-β(3) integrin interaction through antibodies and small molecules targeting either uPAR or β(3) integrin. Our study identifies serum suPAR as a circulating factor that may cause FSGS.
Authors:
Changli Wei; Shafic El Hindi; Jing Li; Alessia Fornoni; Nelson Goes; Junichiro Sageshima; Dony Maiguel; S Ananth Karumanchi; Hui-Kim Yap; Moin Saleem; Qingyin Zhang; Boris Nikolic; Abanti Chaudhuri; Pirouz Daftarian; Eduardo Salido; Armando Torres; Moro Salifu; Minnie M Sarwal; Franz Schaefer; Christian Morath; Vedat Schwenger; Martin Zeier; Vineet Gupta; David Roth; Maria Pia Rastaldi; George Burke; Phillip Ruiz; Jochen Reiser
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-07-31
Journal Detail:
Title:  Nature medicine     Volume:  17     ISSN:  1546-170X     ISO Abbreviation:  Nat. Med.     Publication Date:  2011 Aug 
Date Detail:
Created Date:  2011-08-05     Completed Date:  2011-10-17     Revised Date:  2014-08-20    
Medline Journal Info:
Nlm Unique ID:  9502015     Medline TA:  Nat Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  952-60     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Adolescent
Adult
Animals
Blotting, Western
Female
Flow Cytometry
Glomerulosclerosis, Focal Segmental / blood,  etiology*
Humans
Immunohistochemistry
Immunoprecipitation
Integrin beta3 / metabolism*
Kidney Transplantation / physiology
Male
Mice
Microscopy, Electron
Microscopy, Fluorescence
Models, Biological
Plasmapheresis
Podocytes / metabolism*,  pathology
Receptors, Urokinase Plasminogen Activator / blood*
Grant Support
ID/Acronym/Agency:
DK-82636/DK/NIDDK NIH HHS; DK070011/DK/NIDDK NIH HHS; DK073495/DK/NIDDK NIH HHS; DK089394/DK/NIDDK NIH HHS; R01 DK073495/DK/NIDDK NIH HHS; R01 DK101350/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Integrin beta3; 0/Receptors, Urokinase Plasminogen Activator
Comments/Corrections
Comment In:
Am J Kidney Dis. 2012 Mar;59(3):336-9   [PMID:  22033283 ]
Nat Med. 2011 Aug;17(8):926-7   [PMID:  21818086 ]

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