The evolving story of apolipoprotein L1 nephropathy: the end of the beginning.
The evolving story of apolipoprotein L1 nephropathy: the end of the beginning.
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DOI：
10.1038/s41581-022-00538-3
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发表时间：
2022-05
期刊：
影响因子：
--
通讯作者：
Rosenberg AZ
中科院分区：
文献类型：
--
作者：
Daneshpajouhnejad P;Kopp JB;Winkler CA;Rosenberg AZ
编码载脂蛋白L1（APOL 1）的APOL 1遗传编码变体于2010年被发现，在撒哈拉以南非洲血统的个体中相对常见。大约13%的非洲裔美国人携带两个APOL 1风险等位基因。这些变体称为G1和G2，是肾脏疾病（称为APOL 1肾病）的常见原因，通常表现为局灶节段性肾小球硬化症和高血压和动脉肾硬化症的临床综合征。细胞培养研究表明，APOL 1变体通过几个过程引起细胞功能障碍，包括阳离子通道活性的改变、炎性小体活化、内质网应激增加、蛋白激酶R活化、线粒体功能障碍和APOL 1泛素化的破坏。APOL 1肾病的风险主要限于具有两种APOL 1风险变体的个体。然而，只有少数具有两个APOL 1风险等位基因的个体会发展为肾脏疾病，这表明需要“第二次打击”。造成这种“二次打击”的最佳公认因素是慢性病毒感染，特别是HIV-1，导致干扰素介导的APOL 1启动子激活，尽管大多数APOL 1肾病患者没有明显的辅因子。目前针对APOL 1肾病的疗法不足以阻止慢性肾病的进展，新的靶向分子疗法正在临床试验中。本文综述了目前对APOL 1变异体在肾脏疾病中作用的认识。作者讨论了APOL 1变体的遗传学、蛋白质结构和生物学功能，并概述了有前景的治疗策略。与主要在细胞内的其他APOL家族成员相比，APOL 1含有独特的分泌信号肽，导致其分泌到血浆中。APOL 1肾风险等位基因提供保护免受非洲人类锥虫病，但在携带两个风险等位基因的人中是进行性肾病的风险因素。在美国的非裔美国人中，APOL 1风险等位基因频率约为35%，约13%的个体具有两个风险等位基因;在西非人群及其后代中发现了最高的等位基因频率。细胞和小鼠模型暗示内溶酶体和线粒体功能障碍、改变的离子通道活性、改变的自噬和蛋白激酶R的活化在APOL 1相关肾病的发病机制中;然而，这些损伤途径与人类疾病的相关性尚未得到解决。APOL 1肾病往往是进行性的，目前的标准疗法通常无效;靶向治疗策略最有希望。
Genetic coding variants in APOL1, which encodes apolipoprotein L1 (APOL1), were identified in 2010 and are relatively common among individuals of sub-Saharan African ancestry. Approximately 13% of African Americans carry two APOL1 risk alleles. These variants, termed G1 and G2, are a frequent cause of kidney disease — termed APOL1 nephropathy — that typically manifests as focal segmental glomerulosclerosis and the clinical syndrome of hypertension and arterionephrosclerosis. Cell culture studies suggest that APOL1 variants cause cell dysfunction through several processes, including alterations in cation channel activity, inflammasome activation, increased endoplasmic reticulum stress, activation of protein kinase R, mitochondrial dysfunction and disruption of APOL1 ubiquitinylation. Risk of APOL1 nephropathy is mostly confined to individuals with two APOL1 risk variants. However, only a minority of individuals with two APOL1 risk alleles develop kidney disease, suggesting the need for a ‘second hit’. The best recognized factor responsible for this ‘second hit’ is a chronic viral infection, particularly HIV-1, resulting in interferon-mediated activation of the APOL1 promoter, although most individuals with APOL1 nephropathy do not have an obvious cofactor. Current therapies for APOL1 nephropathies are not adequate to halt progression of chronic kidney disease, and new targeted molecular therapies are in clinical trials. This Review summarizes current understanding of the role of APOL1 variants in kidney disease. The authors discuss the genetics, protein structure and biological functions of APOL1 variants and provide an overview of promising therapeutic strategies. In contrast to other APOL family members, which are primarily intracellular, APOL1 contains a unique secretory signal peptide, resulting in its secretion into plasma. APOL1 renal risk alleles provide protection from African human trypanosomiasis but are a risk factor for progressive kidney disease in those carrying two risk alleles. APOL1 risk allele frequency is ~35% in the African American population in the United States, with ~13% of individuals having two risk alleles; the highest allele frequencies are found in West African populations and their descendants. Cell and mouse models implicate endolysosomal and mitochondrial dysfunction, altered ion channel activity, altered autophagy, and activation of protein kinase R in the pathogenesis of APOL1-associated kidney disease; however, the relevance of these injury pathways to human disease has not been resolved. APOL1 kidney disease tends to be progressive, and current standard therapies are generally ineffective; targeted therapeutic strategies hold the most promise.
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