Apolipoprotein L1 (APOL1) cation current in HEK-293 cells and in human podocytes

Abstract Two heterozygous missense variants (G1 and G2) of Apolipoprotein L1 (APOL1) found in individuals of recent African ancestry can attenuate the severity of infection by some forms of Trypanosoma brucei. However, these two variants within a broader African haplotype also increase the risk of kidney disease in Americans of African descent. Although overexpression of either variant G1 or G2 causes multiple pathogenic changes in cultured cells and transgenic mouse models, the mechanism(s) promoting kidney disease remain unclear. Human serum APOL1 kills trypanosomes through its cation channel activity, and cation channel activity of recombinant APOL1 has been reconstituted in lipid bilayers and proteoliposomes. Although APOL1 overexpression increases whole cell cation currents in HEK-293 cells, the ion channel activity of APOL1 has not been assessed in glomerular podocytes, the major site of APOL1-associated kidney diseases. We characterize APOL1-associated whole cell and on-cell cation currents in HEK-293 T-Rex cells and demonstrate partial inhibition of currents by anti-APOL antibodies. We detect in primary human podocytes a similar cation current inducible by interferon-γ (IFNγ) and sensitive to inhibition by anti-APOL antibody as well as by a fragment of T. brucei Serum Resistance-Associated protein (SRA). CRISPR knockout of APOL1 in human primary podocytes abrogates the IFNγ-induced, antibody-sensitive current. Our novel characterization in HEK-293 cells of heterologous APOL1-associated cation conductance inhibited by anti-APOL antibody and our documentation in primary human glomerular podocytes of endogenous IFNγ-stimulated, APOL1-mediated, SRA and anti-APOL-sensitive ion channel activity together support APOL1-mediated channel activity as a therapeutic target for treatment of APOL1-associated kidney diseases..

Medienart:

E-Artikel

Erscheinungsjahr:

2022

Erschienen:

2022

Enthalten in:

Zur Gesamtaufnahme - volume:475

Enthalten in:

Pflügers Archiv - 475(2022), 3 vom: 30. Nov., Seite 323-341

Sprache:

Englisch

Beteiligte Personen:

Vandorpe, David H. [VerfasserIn]
Heneghan, John F. [VerfasserIn]
Waitzman, Joshua S. [VerfasserIn]
McCarthy, Gizelle M. [VerfasserIn]
Blasio, Angelo [VerfasserIn]
Magraner, Jose M. [VerfasserIn]
Donovan, Olivia G. [VerfasserIn]
Schaller, Lena B. [VerfasserIn]
Shah, Shrijal S. [VerfasserIn]
Subramanian, Balajikarthick [VerfasserIn]
Riella, Cristian V. [VerfasserIn]
Friedman, David J. [VerfasserIn]
Pollak, Martin R. [VerfasserIn]
Alper, Seth L. [VerfasserIn]

Links:

Volltext [lizenzpflichtig]

Themen:

Antibody
Focal Segmental Glomerulosclerosis
Interferon-γ
Patch clamp
Serum resistance-associated

Anmerkungen:

© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2022. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

doi:

10.1007/s00424-022-02767-8

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

OLC2133825363

Zugang & Verfügbarkeit




Zugehörige Publikationen/Bände

    Haven't found what you're looking for?