Departments of Nephrology and Inflammation & Immunity, Cleveland Clinic.
Department of Physiology & Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
Curr Opin Nephrol Hypertens. 2021 May 1;30(3):317-323. doi: 10.1097/MNH.0000000000000704.
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 inducible pluripotent stem cell-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.
目的综述：载脂蛋白 L1（APOL1）基因中的等位基因变异仅存在于非洲裔个体中，可解释非裔美国人患肾病风险增加的大部分原因。然而，尚不清楚与疾病相关的 APOL1 变体如何导致肾脏损伤，也不清楚触发损伤过程的环境应激因子是什么。
最新发现：APOL1 生化和细胞生物学的基础机制研究，加上新的抗体试剂和诱导多能干细胞衍生的细胞系统，集中研究了 APOL1 基因表达诱导时风险变体的细胞毒性作用。由于 APOL1 变体的进化改变了与锥虫血清抗性相关蛋白的关键蛋白-蛋白相互作用，因此开始了其他研究来解决 APOL1 与足细胞中表达的其他蛋白相互作用的差异，包括新的观察结果表明，APOL1 变体可能改变足细胞细胞骨架的动态。
总结：APOL1 各种肾病的发病机制的统一机制仍不清楚且存在争议。由于正在进行的研究一致表明变异蛋白具有致病性功能获得效应，因此抑制 APOL1 蛋白合成或功能的新型治疗药物正在向临床试验推进。
