Apolipoprotein L1 and mechanisms of kidney disease susceptibility.
Apolipoprotein L1 and mechanisms of kidney disease susceptibility.
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DOI：
10.1097/mnh.0000000000000704
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发表时间：
2021-05-01
影响因子：
3.2
通讯作者：
O'Toole JF
中科院分区：
文献类型：
--
作者：
Bruggeman LA;Sedor JR;O'Toole JF
载脂蛋白L1（APOL 1）基因的等位基因变异，仅在非洲血统的个体中发现，解释了非洲裔美国人肾脏疾病的大部分过度风险。然而，对疾病相关的APOL 1变体如何引起肾损伤以及触发损伤过程的环境应激源的身份尚未确定。APOL 1生物化学和细胞生物学的基本机制研究，由新的抗体试剂和iPSC衍生的细胞系统支持，集中在诱导APOL 1基因表达时风险变体的细胞毒性作用。由于APOL 1变异体进化改变了与锥虫血清抗性相关蛋白的关键蛋白质-蛋白质相互作用，其他研究已经开始解决APOL 1与足细胞中表达的其他蛋白质相互作用的差异，包括APOL 1变异体可能改变足细胞细胞骨架动力学的新观察结果。各种APOL 1肾病的统一发病机制仍不清楚且存在争议。由于正在进行的研究一直涉及变异蛋白的致病性功能获得效应，抑制APOL 1蛋白合成或功能的新治疗开发正走向临床试验。
Allelic variants in the gene for apolipoprotein L1 (APOL1), found only in individuals of African ancestry, explain a majority of the excess risk of kidney disease in African Americans. However, a clear understanding how the disease-associated APOL1 variants cause kidney injury and the identity of environmental stressors that trigger the injury process have not been determined. Basic mechanistic studies of APOL1 biochemistry and cell biology, bolstered by new antibody reagents and iPSC-derived cell systems, have focused on the cytotoxic effect of the risk variants when APOL1 gene expression is induced. Since the APOL1 variants evolved to alter a key protein-protein interaction with the trypanosome serum resistance associated protein, additional studies have begun to address differences in APOL1 interactions with other proteins expressed in podocytes, including new observations that APOL1 variants may alter podocyte cytoskeleton dynamics. A unified mechanism of pathogenesis for the various APOL1 nephropathies still remains unclear and controversial. As ongoing studies have consistently implicated the pathogenic gain-of-function effects of the variant proteins, novel therapeutic development inhibiting the synthesis or function of APOL1 proteins is moving toward clinical trials.