ARTICLE: A tripartite complex of suPAR, APOL1 risk variants and αvβ3 integrin on podocytes mediates chronic kidney disease
AUTHORS: Salim S Hayek, Kwi Hye Koh, Morgan E Grams, Changli Wei, Yi-An Ko, Jing Li, Beata Samelko, Hyun Lee, Ranadheer R Dande, Ha Won Lee, Eunsil Hahm, Vasil Peev, Melissa Tracy, Nicholas J Tardi, Vineet Gupta , Mehmet M Altintas, Garrett Garborcauskas, Nikolina Stojanovic, Cheryl A Winkler, Michael S Lipkowitz, Adrienne Tin, Lesley A Inker, Andrew S Levey, Martin Zeier, Barry I Freedman, Jeffrey B Kopp, Karl Skorecki, Josef Coresh, Arshed A Quyyumi, Sanja Sever, Jochen Reiser
JOURNAL: Nat Med. 2017 Aug;23(8):945-953. doi: 10.1038/nm.4362. Epub 2017 Jun 26.
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 APOL1risk 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 APOL1G0. 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.
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Link to abstract online: https://www.ncbi.nlm.nih.gov/pubmed/?term=A+tripartite+complex+of+suPAR%2C+APOL1+risk+variants+and+%CE%B1v%CE%B23+integrin+on+podocytes+mediates+chronic+kidney+disease