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Nat Med. 2017 Aug;23(8):945-953. doi: 10.1038/nm.4362. Epub 2017 Jun 26.

A tripartite complex of suPAR, APOL1 risk variants and αvβ3 integrin on podocytes mediates chronic kidney disease.

Author information

1
Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia, USA.
2
Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA.
3
Welch Center for Prevention and Johns Hopkins Bloomberg School of Public Health, Epidemiology and Clinical Research, Johns Hopkins University, Baltimore, Maryland, USA.
4
Department of Biostatistics and Bioinformatics, Emory University, Atlanta, Georgia, USA.
5
Center for Biomolecular Science and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, Illinois, USA.
6
Harvard Medical School and Division of Nephrology, Massachusetts General Hospital, Charlestown, Massachusetts, USA.
7
Molecular Genetic Epidemiology Section, Basic Research Laboratory, Basic Science Program, NCI, Leidos Biomedical Research, Frederick National Laboratory, Frederick, Maryland, USA.
8
Division of Nephrology and Hypertension, Georgetown University Medical Center, Washington, DC, USA.
9
Division of Nephrology, Tufts Medical Center, Boston, Massachusetts, USA.
10
Division of Nephrology, Ruprecht Karls University, Heidelberg, Germany.
11
Department of Internal Medicine, Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
12
Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
13
Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Rambam Health Care Campus, Haifa, Israel.

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 αvβ3 integrin, whereby APOL1 protein variants G1 and G2 exhibited higher affinity for suPAR-activated avb3 integrin than APOL1 G0. APOL1 G1 or G2 augments αvβ3 integrin activation and causes proteinuria in mice in a suPAR-dependent manner. The synergy of circulating factor suPAR and APOL1 G1 or G2 on αvβ3 integrin activation is a mechanism for CKD.

PMID:
28650456
PMCID:
PMC6019326
DOI:
10.1038/nm.4362
[Indexed for MEDLINE]
Free PMC Article

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