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Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis

Nature Medicine volume 17, pages 952–960 (2011)Cite this article

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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 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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Figure 1: suPAR measurement in the serum of subjects with glomerular disease.
Figure 2: suPAR binds to and activates β3 integrin on podocytes.
Figure 3: suPAR serum concentrations and podocyte β3 integrin activity determine treatment response to plasmapheresis in recurrent FSGS.
Figure 4: suPAR activates β3 integrin and causes foot process effacement in Plaur−/− mouse kidneys and albuminuria in Plaur−/− mice.
Figure 5: Sustained overexpression of suPAR in the blood of wild-type mice leads to an FSGS-like glomerulopathy.
Figure 6: Administration of blocking antibody to uPAR ameliorates suPAR-caused kidney damage.

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Acknowledgements

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. Høyer-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.

Author information

Author notes

  1. Shafic El Hindi, Jing Li and Alessia Fornoni: These authors contributed equally to this work.

Authors and Affiliations

  1. 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

  2. Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, Florida, USA

    Alessia Fornoni

  3. Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA

    Nelson Goes & Boris Nikolic

  4. Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida, USA

    Junichiro Sageshima, George Burke & Phillip Ruiz

  5. Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA

    S Ananth Karumanchi

  6. Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

    Hui-Kim Yap

  7. University of Bristol, Children's Renal Unit, Bristol Royal Hospital for Children, Bristol, UK

    Moin Saleem

  8. Department of Surgery, Columbia University, New York, New York, USA

    Qingyin Zhang

  9. Department of Pediatrics, Stanford University, Stanford, California, USA

    Abanti Chaudhuri & Minnie M Sarwal

  10. The Wallace H. Coulter Center for Translational Research, Miller School of Medicine, University of Miami, Miami, Florida, USA

    Pirouz Daftarian

  11. Department of Ophthalmology, Miller School of Medicine, University of Miami, Miami, Florida, USA

    Pirouz Daftarian

  12. Servicio de Nefrologia and Centre for Biomedical Research on Rare Diseases (CIBERER), Hospital Universitario de Canarias, Canary Islands, Spain

    Eduardo Salido & Armando Torres

  13. Division of Nephrology, SUNY Downstate Medical Center, Brooklyn, New York, USA

    Moro Salifu

  14. Center for Pediatric and Adolescent Medicine, University of Heidelberg, Heidelberg, Germany

    Franz Schaefer

  15. Department of Nephrology and Endocrinology, University of Heidelberg, Heidelberg, Germany

    Christian Morath, Vedat Schwenger & Martin Zeier

  16. Renal Research Laboratory, Fondazione IRCCS Ospedale Maggiore Policlinico & Fondazione D'Amico per la Ricerca sulle Malattie Renali, Milan, Italy

    Maria Pia Rastaldi

  17. Department of Pathology, Miller School of Medicine, University of Miami, Miami, Florida, USA

    Phillip Ruiz

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  1. Changli Wei
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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.

Corresponding author

Correspondence to Jochen Reiser.

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The authors declare no competing financial interests.

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Wei, C., El Hindi, S., Li, J. et al. Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis. Nat Med 17, 952–960 (2011). https://doi.org/10.1038/nm.2411

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