APOL1-G2 accelerates nephrocyte cell death by inhibiting the autophagy pathway.

People of African ancestry carrying the APOL1 risk alleles (RA) G1 or G2 are at high risk of developing kidney diseases through not fully understood mechanisms that impair the function of podocytes. It is also not clear whether the APOL1-G1 and G2 RA affect these cells through similar mechanisms. Previously, we developed transgenic Drosophila fly lines expressing either the human APOL1 reference allele (G0) or APOL1-G1 specifically in nephrocytes, the cells homologous to mammalian podocytes. We found that nephrocytes that expressed the APOL1-G1 RA displayed accelerated cell death, in a manner similar to cultured human podocytes and APOL1 transgenic mouse models. Here, to compare how the APOL1-G1 and G2 RA affect the structure and function of nephrocytes in vivo, we generated nephrocyte-specific transgenic flies that expressed the APOL1-G2 or G1G2 RA (on the same allele). We found that G2 and G1G2-expressing nephrocytes developed more severe changes in autophagic pathways, acidification of organelles, and the structure of the slit diaphragms, compared to G1 nephrocytes, leading to their premature death. We conclude that both RA affect similar key cell trafficking pathways, leading to reduced autophagy, and suggesting new therapeutic targets to prevent APOL1-kidney diseases.