A tripartite complex of suPAR, APOL1 risk variants and alpha(v)beta(3) integrin on podocytes mediates chronic kidney disease

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: APOL1related 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. In individuals of recent African ancestry, variants in APOL1 have been associated with certain forms of CKD. Carriers of two risk alleles (either two of G1 or G2; G1/G1 or G2/G2, or one each of G1 and G2; G1/G2) are at heightened risk for focal segmental glomerulosclerosis (FSGS), HIV-associated nephropathy and hypertension-attributed kidney disease1–5. The molecular mechanisms underlying the association between APOL1 risk variants and CKD remain unclear. Inflammation is thought to be a major contributor to APOL1-related CKD, because APOL1 expression in podocytes is induced by components of innate immune pathways, such as those of interferons and Toll-like receptors6. Moreover, the APOL1 high-risk genotype is strongly associated with nephropathy in people with HIV, a state of immune dysregulation7,8. However, a puzzling observation is that not all individuals carrying the high-risk APOL1 genotype develop renal disease, and equally, not all transgenic animal models, including models of mice9 and zebrafish10, expressing high-risk APOL1 variants display the expected kidney phenotypes. Taken together, these findings suggest the possibility of a ‘second hit’ in the pathogenesis of APOL1-associated nephropathy10. SuPAR is a member of the Ly-6/neurotoxin family of signaling proteins and a marker of immune activation that associates with states of systemic inflammation, such as HIV11–13. Hayek et al. Page 2 Nat Med. Author manuscript; available in PMC 2018 June 26. A uhor M anscript