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Abstract: FR-PO314

Naturally Occurring Variants in APOL1: Channel Activity and Toxicity to Trypanosomes vs. Cultured Cells

Session Information

Category: Genetic Diseases of the Kidneys

  • 1102 Genetic Diseases of the Kidneys: Non-Cystic


  • Edwards, John C., Saint Louis University, Saint Louis, Missouri, United States
  • Winkler, Rebecca L., Saint Louis University, Saint Louis, Missouri, United States
  • Bruno, Jonathan M., Saint Louis University, Saint Louis, Missouri, United States
  • Oliva, Jonathan, Saint Louis University, Saint Louis, Missouri, United States

Wild type ApoL1 (G0) confers resistance to certain African trypanosomes. Two ApoL1 variants (G1, G2) provide resistance to a broader range of trypanosomes and contribute to risk of kidney disease. ApoL1 enters membranes at low pH where it functions as an anion permease. After titration to neutral, ApoL1 transitions to a cation channel. Compared to G0, G1 and G2 have increased cation channel activity and increased toxicity to cultured cells, supporting the hypothesis that this activity contributes to disease. Other ApoL1 variants exist that are inherited as haplotypes. Whether haplotype would impact ApoL1-associated kidney injury is unknown, but haplotype does alter toxicity of ApoL1 expressed in cultured cells.


Purified recombinant G0, G1, and G2 in each of the three major haplotypes were assayed for channel activity and membrane association. A subset of these were assayed for toxicity to Trypansoma brucei brucei and for toxicity to cultured human podocytes using standard assays.


K channel activity for all variants is greatest in the EIK (African) haplotype and least in the EMR (Neanderthal) haplotype. K channel activity of G1 and G2 is about double that of G0 in all haplotypes. The activity variation among haplotypes is not paralleled by differences in membrane association, but activity variation among G0, G1, and G2 is tightly correlated with membrane association. Trypanosome toxicity of G0 variant is greatest in the EIK haplotype and least in the EMR haplotype. G1 variant has no effect on trypanosome toxicity in the EIK haplotype.


Among haplotype encoded isoforms, cation channel activity correlates with toxicity to both trypanosomes and cultured cells but not with membrane association. In contrast, among the disease associated variants, cation channel activity correlates with membrane association and with cultured cell toxicity but not with trypanosome toxicity. The data suggest 1) that differences in cation channel activity among the variants is due to effects on membrane association/insertion, while differences among the haplotypes is due to differences in intrinsic activity of membrane-inserted protein; and 2) either the mechanism of ApoL1 toxicity to trypanosomes and cultured cells may be significantly different, or if identical, is not directly related to the cation channel activity of ApoL1.


  • NIDDK Support