Role of Apolipoprotein L1 in Human Parietal Epithelial Cell Transition
Role of Apolipoprotein L1 in Human Parietal Epithelial Cell Transition
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DOI：
10.1016/j.ajpath.2018.07.025
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发表时间：
2018-11-01
影响因子：
6
通讯作者：
Singhal, Pravin C.
中科院分区：
文献类型：
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作者：
Kumar, Vinod;Vashistha, Himanshu;Singhal, Pravin C.
人壁上皮细胞（佩奇）是维持足细胞稳态的祖细胞。我们假设，载脂蛋白（APO）L1的缺乏确保PEC表型，但其诱导启动PEC转换（足细胞标志物的表达）。APOL 1的表达和miR 193 a的下调与过渡期间足细胞标志物的表达一致。APOL 1的诱导也刺激了人胚肾细胞（具有不可检测的APOL 1蛋白表达的细胞）中的过渡标记。在佩奇中APOL 1沉默上调miR 193 a表达，表明APOL 1和miR 193 a之间存在相互反馈关系的可能性。HIV、干扰素-γ和维生素D受体激动剂下调miR 193 a表达，并诱导佩奇中APOL 1表达沿着转换标记。荧光素酶分析表明miR 193 a和APOL 1之间存在假定的相互作用。由于APOL 1的沉默减弱了HIV-、维生素D受体激动剂-、miR 193 a抑制剂-和干扰素-γ-诱导的过渡标志物的表达，APOL 1似乎是佩奇中miR 193 a-APOL 1轴的关键功能成分。这一观点通过进一步增强PEC标记物在APOL 1 mRNA沉默的佩奇中的表达得到证实。在体内研究中，HIV患者和HIV/APOL 1转基因小鼠的肾小球中有表达突触足蛋白（一种过渡标志物）的佩奇病灶。APOL 1可能通过调节miR 193 a的表达来调节PEC的分子表型，并且APOL 1和miR 193 a具有相互反馈的关系。
Human parietal epithelial cells (PECs) are progenitor cells that sustain podocyte homeostasis. We hypothesized that the lack of apolipoprotein (APO) L1 ensures the PEC phenotype, but its induction initiates PEC transition (expression of podocyte markers). APOL1 expression and down-regulation of miR193a coincided with the expression of podocyte markers during the transition. The induction of APOL1 also stimulated transition markers in human embryonic kidney cells (cells with undetectable APOL1 protein expression). APOL1 silencing in PECs up-regulated miR193a expression, suggesting the possibility of a reciprocal feedback relationship between APOL1 and miR193a. HIV, interferon-gamma, and vitamin D receptor agonist down-regulated miR193a expression and induced APOL1 expression along with transition markers in PECs. Luciferase assay suggested a putative interaction between miR193a and APOL1. Since silencing of APOL1 attenuated HIV-, vitamin D receptor agonist-, miR193a inhibitor-, and interferon-gamma-induced expression of transition markers, APOL1 appears to be a critical functional constituent of the miR193a-APOL1 axis in PECs. This notion was confirmed by further enhanced expression of PEC markers in APOL1 mRNA-silenced PECs. In vivo studies, glomeruli in patients with HIV, and HIV/APOL1 transgenic mice had foci of PECs expressing synaptopodin, a transition marker. APOL1 Likely regulates PEC molecular phenotype through modulation of miR193a expression, and APOL1 and miR193a share a reciprocal feedback relationship.