APOL1 channel blocker reduces proteinuria in FSGS.
APOL1 channel blocker reduces proteinuria in FSGS.
复制标题
APOL1 通道阻滞剂可减少 FSGS 中的蛋白尿。
DOI：
10.1016/j.kint.2023.04.022
复制
发表时间：
2023
影响因子：
19.6
通讯作者：
Olabisi,OpeyemiA
中科院分区：
文献类型：
--
作者：
Olabisi,OpeyemiA
肾脏疾病不是一个机会均等的罪犯。与欧洲血统的个体相比，近期非洲血统的个体，包括非洲裔美国人，具有更高的局灶节段性肾小球硬化症（FSGS）和晚期肾病的风险。1非裔美国人患终末期肾病的比率是白色美国人的4倍，这解释了为什么仅占美国人口13%的黑人占终末期肾病（ESKD）患者的35%以上。2尽管多种因素导致了这种种族差异，但观察到患有FSGS和ESKD的非洲裔美国人往往有肾脏疾病的亲属，这表明遗传因素也参与其中。2008年，两个独立的研究小组报道了22号染色体上的一个特定位点与非裔美国人的FSGS和ESKD相关。3，4对该基因座的进一步研究确定了APOL 1基因的2种编码变体（命名为G1和G2）作为与肾脏疾病相关的驱动因素。尽管APOL1 CKD风险变异与FSGS、高血压相关性肾病和其他形式的CKD的相关性现已得到充分证实，但APOL1风险变异导致肾病的机制仍不清楚。已经提出了几种疾病机制，但尚未达成共识。与参考APOL 1（命名为G0）相比，如我们先前所报道的，APOL 1 G1和G2蛋白形成阳离子通道，异常地将钠转运到细胞中并引起细胞的钾流出。根据该模型，G1和G2而不是G0的异常阳离子转运触发细胞毒性，包括FSGS基础的足细胞损伤。因此，这种变体APOL1特异性功能获得性代表了理想的治疗靶点。
Kidney disease is not an equal opportunity offender. Individuals of recent African ancestry, including African Americans, have a higher risk of focal segmental glomerulosclerosis (FSGS) and advanced stage kidney disease, compared to individuals of European ancestry. 1 African Americans develop end-stage kidney disease at 4 times the rate of White Americans, explaining why Black people, who represent only 13% of the US population, account for more than 35% of people with end-stage kidney disease (ESKD). 2 Although multiple factors contribute to this racial disparity, the observation that African Americans with FSGS and ESKD tend to have relatives with kidney disease suggest that genetic factors are involved. In 2008, 2 independent groups reported that a specific locus on chromosome 22 was associated with FSGS and ESKD in African Americans. 3, 4 Further investigations of this locus identified 2 coding variants of the APOL1 gene (named G1 and G2) as drivers of the association with kidney disease. 5, 6Although the association of APOL1 CKD risk variants with FSGS, hypertension-associated kidney disease, and other forms of CKD is now well established, the mechanism by which APOL1 risk variants cause kidney disease remains unclear. Several disease mechanisms have been proposed, but no consensus has emerged. Compared to the reference APOL1 (named G0), as we previously reported, APOL1 G1 and G2 proteins form cation channels that aberrantly transport sodium into the cell and cause potassium efflux from the cell. According to this model, the aberrant cation transport by G1 and G2 but not G0 triggers cytotoxicity, including podocyte injury that underlies FSGS. 7 Therefore, this variant APOL1-specific gain-of-function represents an ideal therapeutic target.