Naslov
Apolipoprotein L1 Risk Variants and Soluble Urokinase Plasminogen Activator Receptor Synergistically Mediate CKD in African Americans

Autori
Hayek, Salim ; Koh, Kwi Hye ; Grams, Morgan ; Wei, David C. ; Lee, Hyun ; Dande, Ranadheer ; Lee, Ha Won ; Hahm, Eunsil ; Peev, Vasil ; Tardi, Nicholas J. ; Gupta, Vineet ; Altintas, Mehmet M. ; Stojanovic, Nikolina ; Winkler, Cheryl A. ; Lipkowitz, Michael S. ; Tin, Adrienne ; Inker, Lesley ; Levey, Andrew S. ; Zeier, Martin G. ; Freedman, Barry I. ; Kopp, Jeffrey B. ; Skorecki, Karl ; Coresh, Josef ; Sever, Sanja ; Reiser, Jochen

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY ASN Kidney Week 2017 Abstract Supplement / - : Journal of the American Society of Nephrology, 2017, 86-86

Skup
AMERICAN SOCIETY OF NEPHROLOGY Kidney Week 2017

Mjesto i datum
New Orleans (LA), Sjedinjene Američke Države, 31.10.2017. - 05.11.2017

Vrsta sudjelovanja
Ostalo

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
APOL1, suPAR, αvβ3 integrin, chronic kidney disease

Sažetak
Background: Apolipoprotein L1 (APOL1) gene variants G1 and G2 but not the reference allele G0 are associated with an increased risk for chronic kidney disease (CKD) in African Americans, but the mechanisms are unknown. Soluble urokinase plasminogen activator receptor (suPAR) strongly predicts CKD. Methods: We characterized APOL1 genetic variants and plasma suPAR levels in two separate cohorts of African-American patients, the Emory Cardiovascular Biobank (EmCAB ; n = 487) and the African American Study of Kidney Disease and Hypertension (AASK ; n = 607). We studied the biochemical interaction between ApoL1, suPAR, and integrin β3 by immunoprecipitation and surface plasmon resonance (SPR). Results: Here we show that individuals carrying the high-risk APOL1 genotype, i.e. 2 copies of risk variants, manifest a steeper decline in kidney function with increasing suPAR levels compared to individuals harboring low-risk genotypes. SPR identified high affinity interactions between ApoL1, suPAR and αvβ3 integrin. ApoL1 protein variants G1 and G2 exhibited higher affinity for suPAR-activated αvβ3 integrin than ApoL1 G0, and activated podocyte αvβ3 integrin. APOL1 G1 or G2 expression causes proteinuria in mice in a suPAR dependent manner. Conclusions: The synergistic activation of αvβ3 integrin by circulating factor suPAR and ApoL1 G1 or G2 is a mechanism for CKD in patients of recent African ancestry.

Izvorni jezik
Engleski

Znanstvena područja
Biologija

POVEZANOST RADA