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 underlying <i>APOL1</i>-associated renal diseases are unknown. Because the <i>APOL1</i> gene is unique to humans and some primates, new animal models are needed to understand the function of APOL1 <i>in vivo</i> We generated transgenic <i>Drosophila</i> fly lines expressing the human <i>APOL1</i> wild type allele (G0) or the predominant <i>APOL1</i> risk allele (G1) in different tissues. Ubiquitous expression of <i>APOL1</i> G0 or G1 in <i>Drosophila</i> induced lethal phenotypes, and G1 was more toxic than was G0. Selective expression of the <i>APOL1</i> 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 <i>APOL1</i> transgene in nephrocytes also impaired the acidification of organelles. We conclude that expression of an <i>APOL1</i> transgene initially enhances nephrocyte function, causing hypertrophy and subsequent cell death. This new <i>Drosophila</i> 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 <i>APOL1</i>-associated renal diseases.