Nonpodocyte Roles of APOL1 Variants: An Evolving Paradigm.
Nonpodocyte Roles of APOL1 Variants: An Evolving Paradigm.
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DOI：
10.34067/kid.0000000000000216
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发表时间：
2023-09-01
期刊：
影响因子：
--
通讯作者：
Menon MC
中科院分区：
文献类型：
--
作者：
Pell J;Nagata S;Menon MC
自从载脂蛋白L1（APOL 1）中的锥虫溶解外显子变体及其与最近非洲血统个体肾脏疾病的关联的开创性发现以来，出现了广泛的研究，为疾病机制提供了关键见解。重要的是，足细胞已成为我们了解风险基因型如何导致疾病的焦点，足细胞内公认的信号通路的激活被鉴定为在足细胞病、FSGS和进行性肾衰竭中起因果作用。然而，在APOL 1风险个体中基因型到表型进展的完整机制仍不完全清楚。新出现的证据表明，APOL 1风险变体的足细胞内在表达是疾病表现所必需的。本文回顾了将足细胞置于我们理解APOL 1-FSGS中心的开创性数据和报道，以及这种足细胞中心范式的明显缺点。我们研究了可能影响疾病的环境和遗传因素的现有证据，从临床数据和APOL 1作为免疫应答基因的基本作用中得出。我们还回顾了APOL 1对非足细胞（包括内皮细胞、胎盘和免疫细胞）在移植和天然环境中的影响的现有数据。最后，我们讨论了这些新兴数据的影响，以及疾病的范式可能会因此而演变。
Since the seminal discovery of the trypanolytic, exonic variants in apolipoprotein L1 (APOL1) and their association with kidney disease in individuals of recent African ancestry, a wide body of research has emerged offering key insights into the mechanisms of disease. Importantly, the podocyte has become a focal point for our understanding of how risk genotype leads to disease, with activation of putative signaling pathways within the podocyte identified as playing a causal role in podocytopathy, FSGS, and progressive renal failure. However, the complete mechanism of genotype-to-phenotype progression remains incompletely understood in APOL1-risk individuals. An emerging body of evidence reports more than podocyte-intrinsic expression of APOL1 risk variants is needed for disease to manifest. This article reviews the seminal data and reports which placed the podocyte at the center of our understanding of APOL1-FSGS, as well as the evident shortcomings of this podocentric paradigm. We examine existing evidence for environmental and genetic factors that may influence disease, drawing from both clinical data and APOL1's fundamental role as an immune response gene. We also review the current body of data for APOL1's impact on nonpodocyte cells, including endothelial cells, the placenta, and immune cells in both a transplant and native setting. Finally, we discuss the implications of these emerging data and how the paradigm of disease might evolve as a result.
影响因子：
3.6
作者：
Lan, Xiqian;Wen, Hongxiu;Saleem, Moin A.;Mikulak, Joanna;Malhotra, Ashwani;Skorecki, Karl;Singhal, Pravin C.
通讯作者：
Singhal, Pravin C.