Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis |
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Authors: | Wei Changli El Hindi Shafic Li Jing Fornoni Alessia Goes Nelson Sageshima Junichiro Maiguel Dony Karumanchi S Ananth Yap Hui-Kim Saleem Moin Zhang Qingyin Nikolic Boris Chaudhuri Abanti Daftarian Pirouz Salido Eduardo Torres Armando Salifu Moro Sarwal Minnie M Schaefer Franz Morath Christian Schwenger Vedat Zeier Martin Gupta Vineet Roth David Rastaldi Maria Pia Burke George Ruiz Phillip Reiser Jochen |
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Institution: | Department of Medicine, Miller School of Medicine, University of Miami, Miami, Florida, USA. |
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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. |
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