期刊
NATURE MEDICINE
卷 17, 期 8, 页码 952-U70出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.2411
关键词
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资金
- US National Institutes of Health [DK073495, DK089394, DK-82636, DK070011]
- Halpin Foundation-American Society of Nephrology
- American Diabetes Association [7-09-JF-23]
- Diabetes Research Institute Foundation
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 beta(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 beta(3) integrin. Thus, the disease can be abrogated by lowering serum suPAR concentrations through plasmapheresis, or by interfering with the suPAR-beta(3) integrin interaction through antibodies and small molecules targeting either uPAR or beta(3) integrin. Our study identifies serum suPAR as a circulating factor that may cause FSGS.
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