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

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.

APOL1, suPAR, αvβ3 integrin, chronic kidney disease

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