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

  • Ion channels, receptors and transporters
  • Published:
Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

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.

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Data availability

Supporting data are available upon request.

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Acknowledgements

We acknowledge helpful discussions with Dr. Justin Chun (now at the University of Calgary, Calgary, Alberta), Dr. Jiayue Zhang (now at Frontera Therapeutics, Winchester, MA), Dr. Alok K. Sharma (now at Frederick National Laboratory for Cancer Research and Leidos Biomedical Research, Frederick MD), and Dr. Johannes Schlondorff of Beth Israel Deaconess Medical Center and Harvard Medical School (now at the Ohio State University School of Medicine).

Funding

This work was supported by research grants from NIMHD to MRP, SLA, and DJF, and by a grant to MRP from the Ellison Foundation.

Author information

Author notes

  1. John F. Heneghan and Joshua S. Waitzman contributed equally to this article.

Authors and Affiliations

  1. Division of Nephrology and Department of Medicine, Beth Israel Deaconess Medical Center RN380F, 99 Brookline Ave, Boston, MA, 02215, USA

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

  2. Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA

    David H. Vandorpe, Joshua S. Waitzman, Balajikarthick Subramanian, Cristian V. Riella, David J. Friedman, Martin R. Pollak & Seth L. Alper

  3. Broad Institute of Harvard and MIT, Cambridge, MA, 02139, USA

    David J. Friedman, Martin R. Pollak & Seth L. Alper

  4. Department of Pathology, Brigham and Women’s Hospital, Boston, MA, 02215, USA

    John F. Heneghan

  5. Vertex Pharmaceuticals, Boston, MA, 02210, USA

    Gizelle M. McCarthy & Angelo Blasio

  6. San Diego, CA, USA

    Jose M. Magraner

  7. Ludwig-Maximilians-Universitaet, 80336, Munich, Germany

    Lena B. Schaller

  8. Chroma Medicine, Cambridge, MA, 02142, USA

    Shrijal S. Shah

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  1. David H. Vandorpe
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Contributions

David H. Vandorpe, Beth Israel Deaconess Medical Center, Boston, MA, United States: conceived the project, performed experiments, analyzed results, prepared figures, wrote and revised the main manuscript text and reviewed the manuscript.

John F. Heneghan, Beth Israel Deaconess Medical Center, Boston, MA, United States: performed experiments, analyzed results and reviewed the manuscript.

Joshua S. Waitzman, Beth Israel Deaconess Medical Center, Boston, MA, United States: performed experiments, revised the main manuscript text and reviewed the manuscript.

Gizelle M. McCarthy, Beth Israel Deaconess Medical Center, Boston, MA, United States: performed experiments, prepared figures, analyzed results, revised the main manuscript text and reviewed the manuscript.

Angelo Blasio, Beth Israel Deaconess Medical Center, Boston, MA, United States: performed experiments, analyzed results, prepared figures and reviewed the manuscript.

Jose M. Magraner, Beth Israel Deaconess Medical Center, Boston, MA, United States: performed experiments.

Olivia G. Donovan, Beth Israel Deaconess Medical Center, Boston, MA, United States: performed experiments.

Lena B. Schaller, Beth Israel Deaconess Medical Center, Boston, MA, United States: performed experiments.

Shrijal S. Shah, Beth Israel Deaconess Medical Center, Boston, MA, United States: performed experiments, prepared figures and reviewed the manuscript.

Balaji K. Subramanian, Beth Israel Deaconess Medical Center, Boston, MA, United States: performed experiments, prepared figures and reviewed the manuscript.

Cristian V. Riella, Beth Israel Deaconess Medical Center, Boston, MA, United States: performed experiments, analyzed results and reviewed the manuscript.

David J. Friedman, Beth Israel Deaconess Medical Center, Boston, MA, United States: conceived the project, revised the main manuscript text and reviewed the manuscript.

Martin R. Pollak, Beth Israel Deaconess Medical Center, Boston, MA, United States: conceived the project, revised the main manuscript text and reviewed the manuscript.

Seth L. Alper, Beth Israel Deaconess Medical Center, Boston, MA, United States: conceived and oversaw the project, analyzed results, prepared figures, wrote and revised the main manuscript text, reviewed the manuscript.

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Correspondence to Seth L. Alper.

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Co-authors MRP and DJF are inventors on patents related to APOL1, hold equity in Apolo1bio, and have consulted for and received research support from Vertex.

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Vandorpe, D.H., Heneghan, J.F., Waitzman, J.S. et al. Apolipoprotein L1 (APOL1) cation current in HEK-293 cells and in human podocytes. Pflugers Arch - Eur J Physiol 475, 323–341 (2023). https://doi.org/10.1007/s00424-022-02767-8

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