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 α_vβ₃ integrin, whereby APOL1 protein variants G1 and G2 exhibited higher affinity for suPAR-activated avb3 integrin than APOL1 G0. APOL1 G1 or G2 augments α_vβ₃ integrin activation and causes proteinuria in mice in a suPAR-dependent manner. The synergy of circulating factor suPAR and APOL1 G1 or G2 on α_vβ₃ integrin activation is a mechanism for CKD.

中文翻译：

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足细胞上的suPAR，APOL1风险变异体和αvβ3整联蛋白的三联体介导慢性肾脏疾病

可溶性尿激酶纤溶酶原激活物受体（suPAR）独立预测慢性肾脏病（CKD）的发生和发展。载脂蛋白L1（APOL1）基因变体G1和G2，而不是参考等位基因（G0），与非洲近代个体的CKD风险增加相关。在这里，我们显示出两个大型，不相关的队列，即与APOL1风险变异相关的肾功能下降取决于血浆suPAR水平：suPAR较低的患者中APOL1相关的风险降低，而suPAR较高的患者中APOL1相关的风险增强。suPAR的，APOL1和机理上之间，表面等离子体共振研究鉴定高亲和力相互作用α _v β ₃整合素，其中APOL1蛋白变体G1和G2对suPAR激活的avb3整合素的亲和力高于APOL1 G0。APOL1 G1或G2增强件α _v β ₃整联活化并引起蛋白尿小鼠在suPAR的依赖性。对循环因子suPAR的和APOL1 G1或G2的协同α _v β ₃整联激活是CKD的机制。