APOL1-G1 in Nephrocytes Induces Hypertrophy and Accelerates Cell Death
APOL1-G1 in Nephrocytes Induces Hypertrophy and Accelerates Cell Death
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DOI：
10.1681/asn.2016050550
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发表时间：
2017-04-01
影响因子：
13.6
通讯作者：
Han, Zhe
中科院分区：
文献类型：
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作者：
Fu, Yulong;Zhu, Jun-yi;Han, Zhe
携带某些 APOL1 突变等位基因的非洲血统的人患肾脏疾病的风险较高。然而，APOL1 相关肾脏疾病的机制尚不清楚。由于 APOL1 基因是人类和一些灵长类动物所独有的，因此需要新的动物模型来了解 APOL1 在体内的功能。我们生成了在不同组织中表达人类 APOL1 野生型等位基因 (G0) 或主要 APOL1 风险等位基因 (G1) 的转基因果蝇系。 APOL1 G0 或 G1 在果蝇中的普遍表达诱导致死表型，并且 G1 的毒性比 G0 更强。 APOL1 G0 或 G1 转基因在肾细胞、与哺乳动物足细胞同源的果蝇细胞中选择性表达，诱导内吞活性增加以及血淋巴蛋白、葡聚糖颗粒和硝酸银的积累。当带有任一等位基因的转基因果蝇衰老时，肾细胞功能下降，细胞大小增大，并且肾细胞过早死亡。然而，与表达 G0 的细胞相比，表达 G1 的细胞表现出更引人注目的表型，类似于在培养的过表达 APOL1-G1 的哺乳动物足细胞中观察到的表型。在肾细胞中表达 G0 或 G1 APOL1 转基因也会损害细胞器的酸化。我们得出的结论是，APOL1 转基因的表达最初会增强肾细胞功能，导致肾细胞肥大和随后的细胞死亡。这种新的果蝇模型揭示了 APOL1-G1 表达上调可能引发人类肾脏疾病的新机制。此外，该模型可能有助于识别 APOL1 相互作用分子，这些分子可以作为治疗 APOL1 相关肾脏疾病的新药物靶点。
People of African ancestry carrying certain APOL1 mutant alleles are at elevated risk of developing renal diseases. However, the mechanisms underlying APOL1-associated renal diseases are unknown. Because the APOL1 gene is unique to humans and some primates, new animal models are needed to understand the function of APOL1 in vivo. We generated transgenic Drosophila fly lines expressing the human APOL1 wild type allele (G0) or the predominant APOL1 risk allele (G1) in different tissues. Ubiquitous expression of APOL1 G0 or G1 in Drosophila induced lethal phenotypes, and G1 was more toxic than was G0. Selective expression of the APOL1 G0 or G1 transgene in nephrocytes, fly cells homologous to mammalian podocytes, induced increased endocytic activity and accumulation of hemolymph proteins, dextran particles, and silver nitrate. As transgenic flies with either allele aged, nephrocyte function declined, cell size increased, and nephrocytes died prematurely. Compared with G0-expressing cells, however, G1-expressing cells showed more dramatic phenotypes, resembling those observed in cultured mammalian podocytes overexpressing APOL1-G1. Expressing the G0 or G1 APOL1 transgene in nephrocytes also impaired the acidification of organelles. We conclude that expression of an APOL1 transgene initially enhances nephrocyte function, causing hypertrophy and subsequent cell death. This new Drosophila model uncovers a novel mechanism by which upregulated expression of APOL1-G1 could precipitate renal disease in humans. Furthermore, this model may facilitate the identification of APOL1-interacting molecules that could serve as new drug targets to treat APOL1-associated renal diseases.