@article{728185420222436da3f4377a910dcf58,
title = "Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis",
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 β3 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 β3 integrin. Thus, the disease can be abrogated by lowering serum suPAR concentrations through plasmapheresis, or by interfering with the suPAR-2 3 integrin interaction through antibodies and small molecules targeting either uPAR or β3 integrin. Our study identifies serum suPAR as a circulating factor that may cause FSGS.",
author = "Changli Wei and {El Hindi}, Shafic and Jing Li and Alessia Fornoni and Nelson Goes and Junichiro Sageshima and Dony Maiguel and Karumanchi, {S. Ananth} and Yap, {Hui Kim} and Moin Saleem and Qingyin Zhang and Boris Nikolic and Abanti Chaudhuri and Pirouz Daftarian and Eduardo Salido and Armando Torres and Moro Salifu and Sarwal, {Minnie M.} and Franz Schaefer and Christian Morath and Vedat Schwenger and Martin Zeier and Vineet Gupta and David Roth and Rastaldi, {Maria Pia} and George Burke and Phillip Ruiz and Jochen Reiser",
note = "Funding Information: We thank N. Sidenius (Foundation FIRC Institute of Molecular Oncology, Italy) for help with the suPAR assay in mouse samples. We are grateful to L.H. Beck, Jr. and D. Salant (Boston University Medical Center) for providing the membranous nephropathy patient cohort. We thank S. Hsiesh for help with sample collection. We thank G. H{\o}yer-Hansen (the Finsen Laboratory, Denmark) for additional suPAR assays and discussions. The authors are grateful to P.J. Goldschmidt for helpful scientific discussions regarding the manuscript and to M.J. Tracy for critical reading of the manuscript. This work was supported in part by the US National Institutes of Health (grants DK073495 and DK089394 to J.R., DK-82636 to A.F., DK070011 to G.B.), the Halpin Foundation–American Society of Nephrology Research Grant (to C.W.), a grant from the American Diabetes Association (7-09-JF-23 to A.F.), and a grant from the Diabetes Research Institute Foundation (to A.F.). The authors also wish to acknowledge the generous support of the Katz Family Fund.",
year = "2011",
month = aug,
doi = "10.1038/nm.2411",
language = "English (US)",
volume = "17",
pages = "952--960",
journal = "Nature Medicine",
issn = "1078-8956",
publisher = "Nature Research",
number = "8",
}