Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis

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 MorathVedat Schwenger, Martin Zeier, V Gupta, David Roth, Maria Pia Rastaldi, George Burke, Phillip Ruiz, Jochen Reiser

Research output: Contribution to journalArticle (Academic Journal)peer-review

557 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)952-960
JournalNature Medicine
Volume17
Issue number8
Early online date31 Jul 2011
DOIs
Publication statusPublished - Aug 2011

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