Expression of Apolipoprotein L1 Risk Variants at the Plasma Membrane and Haplotype-Dependent Cytotoxicity.

Authors

Oyindamola Christiana Adebayo, Ilhem Dallali, Sara Kerselaers, Sergio Gimeno-Rocafort, Sandra Van Aerschot, Annelies Janssens, Tjessa Bondue, Charlotte Cresens, Nnamdi Joseph Asouzu, Nikky Corthout, Rik Gijsbers, Elena N Levtchenko, Lambertus van den Heuvel, Joris Vriens, Veerle Labarque

Published in

Journal of the American Society of Nephrology : JASN. Jun 15, 2026. Epub Jun 15, 2026.

Abstract

The mechanisms by which apolipoprotein L1 (APOL1) risk variants, G1 and G2, induce kidney disease in individuals of African ancestry remain contentious.
In this study, we utilized a heterologous expression system of HEK-293 cells and human podocytes to investigate APOL1-mediated cytotoxicity using genetic, electrophysiological, and microscopy-based approaches.
APOL1 variants showed dynamic transport in vesicle-like structures towards the plasma membrane via actin filaments. At the plasma membrane, the non-risk APOL1 G0 and risk variants formed non-selective cation-permeable pores for Na+ and Ca2+, exhibiting functional activity under basal conditions. Extracellular Ca2+ was identified as the primary source of Ca2+ influx through APOL1, leading to cytotoxicity. APOL1 risk variants exhibited increased basal channel activity compared to non-risk APOL1 G0, resulting in haplotype-dependent cytotoxicity. Furthermore, we observed that both the M1 (N264K) variant and APOL1 inhibitor, VX-147, exerted protective effects on cell viability by blocking the APOL1-dependent intracellular Ca2+ influx.
This study demonstrated APOL1 to be a membrane protein involved in the influx of Ca2+ from the extracellular medium. Increased activity of APOL1 led to markedly increased cytotoxicity, which supports the gain-of-function theory. This effect was prevented by the presence of N264K variant or treatment with the APOL1 inhibitor VX-147.

PMID:
42295851
Bibliographic data and abstract were imported from PubMed on 15 Jun 2026.

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