Inhibition of the sodium-dependent HCO3- transporter SLC4A4, produces a cystic fibrosis-like airway disease phenotype

  1. Vinciane Saint-Criq
  2. Anita Guequén
  3. Amber R Philp
  4. Sandra Villanueva
  5. Tábata Apablaza
  6. Ignacio Fernández-Moncada
  7. Agustín Mansilla
  8. Livia Delpiano
  9. Iván Ruminot
  10. Cristian Carrasco
  11. Michael A Gray
  12. Carlos A Flores  Is a corresponding author
  1. Université Paris-Saclay, INRAE, France
  2. Centro de Estudios Científicos, Chile
  3. Newcastle University, United Kingdom
  4. Hospital Base Valdivia, Chile

Abstract

Bicarbonate secretion is a fundamental process involved in maintaining acid-base homeostasis. Disruption of bicarbonate entry into airway lumen, as has been observed in cystic fibrosis, produces several defects in lung function due to thick mucus accumulation. Bicarbonate is critical for correct mucin deployment and there is increasing interest in understanding its role in airway physiology, particularly in the initiation of lung disease in children affected by cystic fibrosis, in the absence of detectable bacterial infection. The current model of anion secretion in mammalian airways consists of CFTR and TMEM16A as apical anion exit channels, with limited capacity for bicarbonate transport compared to chloride. However, both channels can couple to SLC26A4 anion exchanger to maximise bicarbonate secretion. Nevertheless, current models lack any details about the identity of the basolateral protein(s) responsible for bicarbonate uptake into airway epithelial cells. We report herein that the electrogenic, sodium-dependent, bicarbonate cotransporter, SLC4A4, is expressed in the basolateral membrane of human and mouse airways, and that it's pharmacological inhibition or genetic silencing reduces bicarbonate secretion. In fully differentiated primary human airway cells cultures, SLC4A4 inhibition induced an acidification of the airways surface liquid and markedly reduced the capacity of cells to recover from an acid load. Studies in the Slc4a4-null mice revealed a previously unreported lung phenotype, characterized by mucus accumulation and reduced mucociliary clearance. Collectively, our results demonstrate that the reduction of SLC4A4 function induced a CF-like phenotype, even when chloride secretion remained intact, highlighting the important role SLC4A4 plays in bicarbonate secretion and mammalian airway function.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting file.

Article and author information

Author details

  1. Vinciane Saint-Criq

    Université Paris-Saclay, INRAE, Jouy-en-Josas, France
    Competing interests
    The authors declare that no competing interests exist.
  2. Anita Guequén

    Centro de Estudios Científicos, Valdivia, Chile
    Competing interests
    The authors declare that no competing interests exist.
  3. Amber R Philp

    Centro de Estudios Científicos, Valdivia, Chile
    Competing interests
    The authors declare that no competing interests exist.
  4. Sandra Villanueva

    Centro de Estudios Científicos, Valdivia, Chile
    Competing interests
    The authors declare that no competing interests exist.
  5. Tábata Apablaza

    Centro de Estudios Científicos, Valdivia, Chile
    Competing interests
    The authors declare that no competing interests exist.
  6. Ignacio Fernández-Moncada

    Centro de Estudios Científicos, Valdivia, Chile
    Competing interests
    The authors declare that no competing interests exist.
  7. Agustín Mansilla

    Centro de Estudios Científicos, Valdivia, Chile
    Competing interests
    The authors declare that no competing interests exist.
  8. Livia Delpiano

    Biosciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2319-4456
  9. Iván Ruminot

    Centro de Estudios Científicos, Valdivia, Chile
    Competing interests
    The authors declare that no competing interests exist.
  10. Cristian Carrasco

    Hospital Base Valdivia, Valdivia, Chile
    Competing interests
    The authors declare that no competing interests exist.
  11. Michael A Gray

    Biosciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  12. Carlos A Flores

    Centro de Estudios Científicos, Valdivia, Chile
    For correspondence
    cflores@cecs.cl
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3813-1909

Funding

CF Trust Strategic Research Centre (SRC003)

  • Michael A Gray

CF Trust Strategic Reserach Centre (SRC013)

  • Michael A Gray

Medical Research Council (MC_PC_15030)

  • Michael A Gray

Fondo Nacional de Desarrollo Científico y Tecnológico (1221257)

  • Carlos A Flores

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. László Csanády, Semmelweis University, Hungary

Ethics

Animal experimentation: Unless otherwise stated, all procedures were performed after mice were deeply anesthetized via i.p. injection of 120 mg/kg ketamine and 16 mg/kg xylazine followed by exsanguination. All experimental procedures were approved by the Centro de Estudios Científicos (CECs) Institutional Animal Care and Use Committee (#2015-02) and are in accordance with relevant guidelines and regulations.

Version history

  1. Received: November 25, 2021
  2. Preprint posted: December 16, 2021 (view preprint)
  3. Accepted: May 27, 2022
  4. Accepted Manuscript published: May 30, 2022 (version 1)
  5. Version of Record published: June 7, 2022 (version 2)

Copyright

© 2022, Saint-Criq et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Vinciane Saint-Criq
  2. Anita Guequén
  3. Amber R Philp
  4. Sandra Villanueva
  5. Tábata Apablaza
  6. Ignacio Fernández-Moncada
  7. Agustín Mansilla
  8. Livia Delpiano
  9. Iván Ruminot
  10. Cristian Carrasco
  11. Michael A Gray
  12. Carlos A Flores
(2022)
Inhibition of the sodium-dependent HCO3- transporter SLC4A4, produces a cystic fibrosis-like airway disease phenotype
eLife 11:e75871.
https://doi.org/10.7554/eLife.75871

Share this article

https://doi.org/10.7554/eLife.75871

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