| Literature DB >> 28650456 |
Salim S Hayek1, Kwi Hye Koh2, Morgan E Grams3, Changli Wei2, Yi-An Ko4, Jing Li2, Beata Samelko2, Hyun Lee5, Ranadheer R Dande2, Ha Won Lee2, Eunsil Hahm2, Vasil Peev2, Melissa Tracy2, Nicholas J Tardi2, Vineet Gupta2, Mehmet M Altintas2, Garrett Garborcauskas6, Nikolina Stojanovic6, Cheryl A Winkler7, Michael S Lipkowitz8, Adrienne Tin3, Lesley A Inker9, Andrew S Levey9, Martin Zeier10, Barry I Freedman11, Jeffrey B Kopp12, Karl Skorecki13, Josef Coresh3, Arshed A Quyyumi1, Sanja Sever6, Jochen Reiser2.
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.Entities:
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Year: 2017 PMID： 28650456 PMCID： PMC6019326 DOI： 10.1038/nm.4362
Source DB: PubMed Journal: Nat Med ISSN： 1078-8956 Impact factor: 53.440