title: APOL1-G1 in Nephrocytes Induces Hypertrophy and Accelerates Cell Death.
abstract: People of African ancestry carrying certain APOL1 mutant alleles are at elevated risk of developing renal diseases. However, the mechanisms underlyingAPOL1-associated renal diseases are unknown. Because theAPOL1gene is unique to humans and some primates, new animal models are needed to understand the function of APOL1in vivoWe generated transgenicDrosophilafly lines expressing the humanAPOL1wild type allele (G0) or the predominantAPOL1risk allele (G1) in different tissues. Ubiquitous expression ofAPOL1G0 or G1 inDrosophilainduced lethal phenotypes, and G1 was more toxic than was G0. Selective expression of theAPOL1G0 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 G1APOL1transgene in nephrocytes also impaired the acidification of organelles. We conclude that expression of anAPOL1transgene initially enhances nephrocyte function, causing hypertrophy and subsequent cell death. This newDrosophilamodel 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 treatAPOL1-associated renal diseases.
authors.affiliation: Center for Cancer and Immunology Research, Washington, DC.
authors.forename: Yulong
authors.initials: Y
authors.lastname: Fu
authors.affiliation: Center for Cancer and Immunology Research, Washington, DC.
authors.forename: Jun-Yi
authors.initials: JY
authors.lastname: Zhu
authors.affiliation: Center for Cancer and Immunology Research, Washington, DC.
authors.forename: Adam
authors.initials: A
authors.lastname: Richman
authors.affiliation: Center for Cancer and Immunology Research, Washington, DC.|Center for Genetic Medicine Research, Washington, DC.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Center for Genetic Medicine Research, Washington, DC.
authors.forename: Xuefang
authors.initials: X
authors.lastname: Xie
authors.affiliation: Center for Genetic Medicine Research, Washington, DC.|Division of Nephrology, Children's National Health Systems, Washington, DC; and.|Department of Pediatrics, The George Washington University School of Medicine and Health Sciences, Washington, DC.
authors.forename: Jharna R
authors.initials: JR
authors.lastname: Das
authors.affiliation: Center for Genetic Medicine Research, Washington, DC.|Department of Pediatrics, The George Washington University School of Medicine and Health Sciences, Washington, DC.
authors.forename: Jinliang
authors.initials: J
authors.lastname: Li
authors.affiliation: Center for Genetic Medicine Research, Washington, DC.|Division of Nephrology, Children's National Health Systems, Washington, DC; and.|Department of Pediatrics, The George Washington University School of Medicine and Health Sciences, Washington, DC.
authors.forename: Patricio E
authors.initials: PE
authors.lastname: Ray
authors.affiliation: Center for Cancer and Immunology Research, Washington, DC; ZHan@childrensnational.org pray@childrensnational.org.|Department of Pediatrics, The George Washington University School of Medicine and Health Sciences, Washington, DC.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Han
mesh_terms: D000483:Alleles; D000818:Animals; D030801:Animals, Genetically Modified; D000075944:Apolipoprotein L1; D001053:Apolipoproteins / Q000235:genetics*; D016923:Cell Death / Q000502:physiology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018450:Disease Progression; D004330:Drosophila; D005786:Gene Expression Regulation; D006801:Humans; D006984:Hypertrophy / Q000235:genetics; D007668:Kidney / Q000473:pathology*; D007674:Kidney Diseases / Q000235:genetics* / Q000473:pathology; D008075:Lipoproteins, HDL / Q000235:genetics*
chemical_list: C108666:APOL1 protein, human; D000075944:Apolipoprotein L1; D001053:Apolipoproteins; D008075:Lipoproteins, HDL
keywords: cell biology and structure; cell survival; chronic kidney disease; genetic renal disease