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 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.
authors.affiliation: Department of Medicine, Miller School of Medicine, University of Miami, Miami, Florida, USA.
authors.forename: Changli
authors.initials: C
authors.lastname: Wei
authors.forename: Shafic
authors.initials: S
authors.lastname: El Hindi
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Alessia
authors.initials: A
authors.lastname: Fornoni
authors.forename: Nelson
authors.initials: N
authors.lastname: Goes
authors.forename: Junichiro
authors.initials: J
authors.lastname: Sageshima
authors.forename: Dony
authors.initials: D
authors.lastname: Maiguel
authors.forename: S Ananth
authors.initials: SA
authors.lastname: Karumanchi
authors.forename: Hui-Kim
authors.initials: HK
authors.lastname: Yap
authors.forename: Moin
authors.initials: M
authors.lastname: Saleem
authors.forename: Qingyin
authors.initials: Q
authors.lastname: Zhang
authors.forename: Boris
authors.initials: B
authors.lastname: Nikolic
authors.forename: Abanti
authors.initials: A
authors.lastname: Chaudhuri
authors.forename: Pirouz
authors.initials: P
authors.lastname: Daftarian
authors.forename: Eduardo
authors.initials: E
authors.lastname: Salido
authors.forename: Armando
authors.initials: A
authors.lastname: Torres
authors.forename: Moro
authors.initials: M
authors.lastname: Salifu
authors.forename: Minnie M
authors.initials: MM
authors.lastname: Sarwal
authors.forename: Franz
authors.initials: F
authors.lastname: Schaefer
authors.forename: Christian
authors.initials: C
authors.lastname: Morath
authors.forename: Vedat
authors.initials: V
authors.lastname: Schwenger
authors.forename: Martin
authors.initials: M
authors.lastname: Zeier
authors.forename: Vineet
authors.initials: V
authors.lastname: Gupta
authors.forename: David
authors.initials: D
authors.lastname: Roth
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Rastaldi
authors.forename: George
authors.initials: G
authors.lastname: Burke
authors.forename: Phillip
authors.initials: P
authors.lastname: Ruiz
authors.forename: Jochen
authors.initials: J
authors.lastname: Reiser
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D015153:Blotting, Western; D005260:Female; D005434:Flow Cytometry; D005923:Glomerulosclerosis, Focal Segmental / Q000097:blood / Q000209:etiology*; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D039661:Integrin beta3 / Q000378:metabolism*; D016030:Kidney Transplantation / Q000502:physiology; D008297:Male; D051379:Mice; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D010956:Plasmapheresis; D050199:Podocytes / Q000378:metabolism* / Q000473:pathology; D055293:Receptors, Urokinase Plasminogen Activator / Q000097:blood*
chemical_list: D039661:Integrin beta3; D055293:Receptors, Urokinase Plasminogen Activator