Nature Medicine | Article
Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis
- Changli Wei1,
- Shafic El Hindi1, 18,
- Jing Li1, 18,
- Alessia Fornoni1, 2, 18,
- Nelson Goes3,
- Junichiro Sageshima4,
- Dony Maiguel1,
- S Ananth Karumanchi5,
- Hui-Kim Yap6,
- Moin Saleem7,
- Qingyin Zhang8,
- Boris Nikolic3,
- Abanti Chaudhuri9,
- Pirouz Daftarian10, 11,
- Eduardo Salido12,
- Armando Torres12,
- Moro Salifu13,
- Minnie M Sarwal9,
- Franz Schaefer14,
- Christian Morath15,
- Vedat Schwenger15,
- Martin Zeier15,
- Vineet Gupta1,
- David Roth1,
- Maria Pia Rastaldi16,
- George Burke4,
- Phillip Ruiz4, 17,
- Jochen Reiser1,
- Journal name:
- Nature Medicine
- Volume:
- 17,
- Pages:
- 952–960
- Year published:
- DOI:
- doi:10.1038/nm.2411
- Received
- Accepted
- Published online
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–β3 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.
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References
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Author information
Primary authors
These authors contributed equally to this work.
- Shafic El Hindi,
- Jing Li &
- Alessia Fornoni
Affiliations
-
Department of Medicine, Miller School of Medicine, University of Miami, Miami, Florida, USA.
- Changli Wei,
- Shafic El Hindi,
- Jing Li,
- Alessia Fornoni,
- Dony Maiguel,
- Vineet Gupta,
- David Roth &
- Jochen Reiser
-
Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, Florida, USA.
- Alessia Fornoni
-
Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
- Nelson Goes &
- Boris Nikolic
-
Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida, USA.
- Junichiro Sageshima,
- George Burke &
- Phillip Ruiz
-
Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.
- S Ananth Karumanchi
-
Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
- Hui-Kim Yap
-
University of Bristol, Children's Renal Unit, Bristol Royal Hospital for Children, Bristol, UK.
- Moin Saleem
-
Department of Surgery, Columbia University, New York, New York, USA.
- Qingyin Zhang
-
Department of Pediatrics, Stanford University, Stanford, California, USA.
- Abanti Chaudhuri &
- Minnie M Sarwal
-
The Wallace H. Coulter Center for Translational Research, Miller School of Medicine, University of Miami, Miami, Florida, USA.
- Pirouz Daftarian
-
Department of Ophthalmology, Miller School of Medicine, University of Miami, Miami, Florida, USA.
- Pirouz Daftarian
-
Servicio de Nefrologia and Centre for Biomedical Research on Rare Diseases (CIBERER), Hospital Universitario de Canarias, Canary Islands, Spain.
- Eduardo Salido &
- Armando Torres
-
Division of Nephrology, SUNY Downstate Medical Center, Brooklyn, New York, USA.
- Moro Salifu
-
Center for Pediatric and Adolescent Medicine, University of Heidelberg, Heidelberg, Germany.
- Franz Schaefer
-
Department of Nephrology and Endocrinology, University of Heidelberg, Heidelberg, Germany.
- Christian Morath,
- Vedat Schwenger &
- Martin Zeier
-
Renal Research Laboratory, Fondazione IRCCS Ospedale Maggiore Policlinico & Fondazione D'Amico per la Ricerca sulle Malattie Renali, Milan, Italy.
- Maria Pia Rastaldi
-
Department of Pathology, Miller School of Medicine, University of Miami, Miami, Florida, USA.
- Phillip Ruiz
Contributions
J.R. conceived the study. J.R. and C.W. designed the experiments, coordinated the study, analyzed the data and wrote the manuscript. C.W., S.E.H., J.L., D.M., Q.Z., B.N., P.D., V.G. performed the experiments. A.F., N.G., G.B., J.S., S.A.K., H.-K.Y., M.Saleem, A.C., E.S., A.T., M.Salifu, M.M.S., F.S., C.M., V.S., M.Z., D.R., M.P.R., P.R., J.R. contributed to clinical samples and clinical information. M.P.R. and P.R. provided pathology service.
Competing financial interests
The authors declare no competing financial interests.
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Changli Wei
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Shafic El Hindi
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Jing Li
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Alessia Fornoni
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Nelson Goes
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Junichiro Sageshima
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Dony Maiguel
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S Ananth Karumanchi
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Hui-Kim Yap
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Moin Saleem
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Qingyin Zhang
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Boris Nikolic
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Abanti Chaudhuri
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Pirouz Daftarian
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Armando Torres
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Moro Salifu
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Minnie M Sarwal
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Franz Schaefer
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Christian Morath
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Vedat Schwenger
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Martin Zeier
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David Roth
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Supplementary information
PDF files
- Supplementary Text and Figures (688K)
Supplementary Figures 1–3, Supplementary Tables 1–3 and Supplementary Methods