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

Elife. 2022 May 30;11:e75871. doi: 10.7554/eLife.75871.

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.

Keywords: Slc4a4; airways; cell biology; human; medicine; mouse; mucus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anion Exchange Protein 1, Erythrocyte / metabolism*
  • Bicarbonates / metabolism
  • Chlorides / metabolism
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics
  • Cystic Fibrosis*
  • Mammals / metabolism
  • Mice
  • Phenotype
  • Sodium / metabolism
  • Sodium-Bicarbonate Symporters / genetics

Substances

  • Anion Exchange Protein 1, Erythrocyte
  • Bicarbonates
  • Chlorides
  • Slc4a1 protein, mouse
  • Sodium-Bicarbonate Symporters
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Sodium