Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis

• Published in: Nature medicine Vol. 17; no. 8; pp. 952 - 960
• Main 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
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.08.2011; Nature Publishing Group
• Subjects: 692/53; 692/699/1585/2759/1523; 692/700/565/545/576/402; Adolescent; Adult; Animals; Biomedical and Life Sciences; Biomedicine; Blotting, Western; Cancer Research; Development and progression; Diagnosis; Female; Flow Cytometry; Glomerulosclerosis, Focal Segmental - blood; Glomerulosclerosis, Focal Segmental - etiology; Humans; Immunohistochemistry; Immunoprecipitation; Infectious Diseases; Integrin beta3 - metabolism; Kidney diseases; Kidney Transplantation - physiology; Kidneys; Male; Metabolic Diseases; Mice; Microscopy, Electron; Microscopy, Fluorescence; Models, Biological; Molecular Medicine; Neurons; Neurosciences; Pathogenesis; Physiological aspects; Plasmapheresis; Podocytes - metabolism; Podocytes - pathology; Receptors, Urokinase Plasminogen Activator - blood; Risk factors; Sclerosis; Transplantation; Transplants & implants; Urokinase; United States
• ISSN: 1078-8956; 1546-170X; 1546-170X
• DOI: 10.1038/nm.2411

Focal segmental glomerulosclerosis (FSGS), or kidney scarring, is difficult to treat and is often only curable with kidney transplantation. However, FSGS often recurs after transplantation, and ~40 years ago, an unknown soluble factor in the recipient was hypothesized to exist to explain such cases. Jochen Reiser and his colleagues use data from human and mouse studies to show that soluble uPAR may be the long-sought-after soluble factor. 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.