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Pendrin mediates bicarbonate secretion and enhances CFTR function in airway surface epithelia

Abstract : Bicarbonate facilitates mucin unpacking and bacterial killing; however, its transport mechanisms in the airways are not well understood. cAMP stimulates anion efflux through the cystic fibrosis (CF) transmembrane conductance regulator (CFTR; ABCC7) anion channel, and this is defective in CF. The anion exchanger pendrin (SLC26A4) also mediates HCO3− efflux and is upregulated by proinflammatory cytokines. Here, we examined pendrin and CFTR expression and their contributions to HCO3− secretion by human nasal and bronchial epithelia. In native tissue, both proteins were most abundant at the apical pole of ciliated surface cells with little expression in submucosal glands. In well-differentiated primary nasal and bronchial cell cultures, IL-4 dramatically increased pendrin mRNA levels and apical immunostaining. Exposure to low-Cl− apical solution caused intracellular alkalinization (ΔpHi) that was enhanced fourfold by IL-4 pretreatment. ΔpHi was unaffected by 4,4′-diisothiocyano-2,2′-stilbenedisulfonic acid (DIDS) or CFTR inhibitor CFTRinh-172, but was reduced by adenoviral shRNA targeting pendrin. Forskolin increased ΔpHi, and this stimulation was prevented by CFTRinh-172, implicating CFTR, yet forskolin only increased ΔpHi after pendrin expression had been induced by IL-4. The dependence of ΔpHi on pendrin suggests there is minimal electrical coupling between Cl− and HCO3− fluxes and that CFTR activation increases anion exchange–mediated HCO3− influx. Conversely, inducing pendrin expression increased forskolin-stimulated, CFTRinh-172–sensitive current by approximately twofold in epithelial and nonepithelial cells. We conclude that pendrin mediates most HCO3− secretion across airway surface epithelium during inflammation and enhances electrogenic Cl− secretion via CFTR, as described for other SLC26A transporters.
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Submitted on : Thursday, February 18, 2021 - 2:28:11 PM
Last modification on : Thursday, February 18, 2021 - 2:47:25 PM
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Dusik Kim, Junwei Huang, Arnaud Billet, Asmahan Abu-Arish, Julie Goepp, et al.. Pendrin mediates bicarbonate secretion and enhances CFTR function in airway surface epithelia. American Journal of Respiratory Cell and Molecular Biology, American Thoracic Society, 2019, 60 (6), pp.705-716. ⟨10.1165/rcmb.2018-0158OC⟩. ⟨hal-03145546⟩

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