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A tripartite complex of suPAR, APOL1 risk variants and αvß3 integrin on podocytes mediates chronic kidney disease.
Hayek, Salim S; Koh, Kwi Hye; Grams, Morgan E; Wei, Changli; Ko, Yi-An; Li, Jing; Samelko, Beata; Lee, Hyun; Dande, Ranadheer R; Lee, Ha Won; Hahm, Eunsil; Peev, Vasil; Tracy, Melissa; Tardi, Nicholas J; Gupta, Vineet; Altintas, Mehmet M; Garborcauskas, Garrett; Stojanovic, Nikolina; Winkler, Cheryl A; Lipkowitz, Michael S; Tin, Adrienne; Inker, Lesley A; Levey, Andrew S; Zeier, Martin; Freedman, Barry I; Kopp, Jeffrey B; Skorecki, Karl; Coresh, Josef; Quyyumi, Arshed A; Sever, Sanja; Reiser, Jochen.
Afiliação
  • Hayek SS; Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia, USA.
  • Koh KH; Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA.
  • Grams ME; Welch Center for Prevention and Johns Hopkins Bloomberg School of Public Health, Epidemiology and Clinical Research, Johns Hopkins University, Baltimore, Maryland, USA.
  • Wei C; Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA.
  • Ko YA; Department of Biostatistics and Bioinformatics, Emory University, Atlanta, Georgia, USA.
  • Li J; Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA.
  • Samelko B; Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA.
  • Lee H; Center for Biomolecular Science and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, Illinois, USA.
  • Dande RR; Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA.
  • Lee HW; Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA.
  • Hahm E; Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA.
  • Peev V; Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA.
  • Tracy M; Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA.
  • Tardi NJ; Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA.
  • Gupta V; Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA.
  • Altintas MM; Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA.
  • Garborcauskas G; Harvard Medical School and Division of Nephrology, Massachusetts General Hospital, Charlestown, Massachusetts, USA.
  • Stojanovic N; Harvard Medical School and Division of Nephrology, Massachusetts General Hospital, Charlestown, Massachusetts, USA.
  • Winkler CA; Molecular Genetic Epidemiology Section, Basic Research Laboratory, Basic Science Program, NCI, Leidos Biomedical Research, Frederick National Laboratory, Frederick, Maryland, USA.
  • Lipkowitz MS; Division of Nephrology and Hypertension, Georgetown University Medical Center, Washington, DC, USA.
  • Tin A; Welch Center for Prevention and Johns Hopkins Bloomberg School of Public Health, Epidemiology and Clinical Research, Johns Hopkins University, Baltimore, Maryland, USA.
  • Inker LA; Division of Nephrology, Tufts Medical Center, Boston, Massachusetts, USA.
  • Levey AS; Division of Nephrology, Tufts Medical Center, Boston, Massachusetts, USA.
  • Zeier M; Division of Nephrology, Ruprecht Karls University, Heidelberg, Germany.
  • Freedman BI; Department of Internal Medicine, Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
  • Kopp JB; Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
  • Skorecki K; Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Rambam Health Care Campus, Haifa, Israel.
  • Coresh J; Welch Center for Prevention and Johns Hopkins Bloomberg School of Public Health, Epidemiology and Clinical Research, Johns Hopkins University, Baltimore, Maryland, USA.
  • Quyyumi AA; Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia, USA.
  • Sever S; Harvard Medical School and Division of Nephrology, Massachusetts General Hospital, Charlestown, Massachusetts, USA.
  • Reiser J; Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA.
Nat Med ; 23(8): 945-953, 2017 Aug.
Article em En | MEDLINE | ID: mdl-28650456
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 αvß3 integrin, whereby APOL1 protein variants G1 and G2 exhibited higher affinity for suPAR-activated avb3 integrin than APOL1 G0. APOL1 G1 or G2 augments αvß3 integrin activation and causes proteinuria in mice in a suPAR-dependent manner. The synergy of circulating factor suPAR and APOL1 G1 or G2 on αvß3 integrin activation is a mechanism for CKD.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Apolipoproteínas / Proteinúria / Integrina alfaVbeta3 / Podócitos / Insuficiência Renal Crônica / Receptores de Ativador de Plasminogênio Tipo Uroquinase / Lipoproteínas HDL Idioma: En Ano de publicação: 2017 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Apolipoproteínas / Proteinúria / Integrina alfaVbeta3 / Podócitos / Insuficiência Renal Crônica / Receptores de Ativador de Plasminogênio Tipo Uroquinase / Lipoproteínas HDL Idioma: En Ano de publicação: 2017 Tipo de documento: Article