A tripartite complex of suPAR, APOL1 risk variants and alpha(v)beta(3) integrin on podocytes mediates chronic kidney disease

• Type of Material: Article
• Authors: Salim S. Hayek, Emory University; Kwi Hye Koh, Rush University; Morgan E. Grams, Johns Hopkins University; Changli Wei, Rush University; Jing Li, Rush Univesity; Yi-An Ko, Emory University; Beata Samelko, Rush University; Hyun Lee, University of Illinois; Ranadheer R. Dande, Rush University; Ha Won Lee, Rush University; Eunsil Hahm, Rush University; Vasil Peev, Rush University; Melissa Tracy, Rush University; Nicholas J. Tardi, Rush University; Vineet Gupta, Rush University; Mehmet M. Altintas, Rush University; Garrett Garborcauskas, Massachusetts General Hospital; Nikolina Stojanovic, Massachusetts General Hospital; Cheryl A. Winkler, Frederick National Laboratory; Michael S. Lipkowitz, Georgetown University; Adrienne Tin, Johns Hopkins University; Lesley A. Inker, Tufts Medical Center; Andrew S. Levey, Tufts Medical Center; Martin Zeier, Ruprecht Karls University; Barry I. Freedman, Wake Forest University; Jeffrey B. Kopp, National Institutes of Health; Karl Skorecki, Technion–Israel Institute of Technology; Josef Coresh, Johns Hopkins University; Arshed Quyyumi, Emory University; Sanja Sever, Massachusetts General Hospital
• Language: English
• Date: 2017-08-01
• Publisher: Nature Research (part of Springer Nature)
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017 Nature America, Inc., part of Springer Nature. All rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1038/nm.4362
• Title of Journal or Parent Work: Nature Medicine
• ISSN: 1078-8956
• Volume: 23
• Issue: 8
• Start Page: 945
• End Page: +
• Grant/Funding Information: J.R. is supported by grants 5R01DK101350-03 (NIDDK) and 1R01DK106051 (NIDDK); This project has also been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN26120080001E.; J.C., A.S.L. and L.A.I. are supported by grant R01DK087961 (NIH).; A.A.Q. is supported by grants 5P01HL101398-02, 1P20HL113451-01, 1R56HL126558-01, 1RF1AG051633-01, R01 NS064162-01, R01 HL89650-01, HL095479-01, 1U10HL110302-01, 1DP3DK094346-01, 2P01HL086773-06A1 (NIH).; Funding for the collection and management of samples was received from the Robert W. Woodruff Health Sciences Center Fund (Atlanta, GA), Emory Heart and Vascular Center (Atlanta, GA), Katz Family Foundation Preventive Cardiology Grant (Atlanta, GA), and National Institutes of Health (NIH) Grants UL1 RR025008 from the Clinical and Translational Science Award program and the Intramural Research Programs of NCI and NIDDK, NIH.; M.E.G., J.C., A.S.L., L.A.I. and A.T. are supported by grants R01DK108803 (NIH) and U01DK085689 (NIDDK).; E.H. was supported by grant 1RO1 DK106051.; This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.
• Keywords: ENDOCYTOSIS; Science & Technology; PROTEIN; Life Sciences & Biomedicine; Research & Experimental Medicine; Medicine, Research & Experimental; AFRICAN-AMERICANS; NEPHROPATHY; SOLUBLE UROKINASE RECEPTOR; PLASMINOGEN-ACTIVATOR RECEPTOR; Cell Biology; APOLIPOPROTEIN L1; UPAR; Biochemistry & Molecular Biology; FOCAL SEGMENTAL GLOMERULOSCLEROSIS; CELL-DEATH
• Research Categories: Biology, Biostatistics; Health Sciences, Medicine and Surgery

Abstract

Soluble urokinase plasminogen activator receptor (suPAR) independently predicts chronic kidney disease (CKD) incidence and progression. Apolipoprotein L1 (APOL1) gene variants G1 and G2, but not the reference allele (G0), are associated with an increased risk of CKD in individuals of recent African ancestry. Here we show in two large, unrelated cohorts that decline in kidney function associated with APOL1 risk variants was dependent on plasma suPAR levels: APOL1-related risk was attenuated in patients with lower suPAR, and strengthened in those with higher suPAR levels. Mechanistically, surface plasmon resonance studies identified high-affinity interactions between suPAR, APOL1 and α v β 3 integrin, whereby APOL1 protein variants G1 and G2 exhibited higher affinity for suPAR-activated avb3 integrin than APOL1 G0. APOL1 G1 or G2 augments α v β 3 integrin activation and causes proteinuria in mice in a suPAR-dependent manner. The synergy of circulating factor suPAR and APOL1 G1 or G2 on α v β 3 integrin activation is a mechanism for CKD.