Pendrin Mediates Bicarbonate Secretion and Enhances Cystic Fibrosis Transmembrane Conductance Regulator 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 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 4‐fold by IL‐4 pretreatment. ΔpHi was unaffected by DIDS or 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 ~2‐fold in epithelial and non‐epithelial 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. Support or Funding Information Support: Cystic Fibrosis Canada, Canadian Institutes of Health Research, Canada Foundation for Innovation This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Transport properties in CFTR−/− knockout piglets suggest normal airway surface liquid pH and enhanced amiloride-sensitive Na+ absorption

“…6c,d). These data along with previous studies suggest that pendrin-dependent HCO 3 − secretion may be more important in controlling ASL pH [11,27,50]. We are confident that our intrabronchial microelectrode measurements were correct, as the standard curve obtained with this electrode provided reliable and reproducible pH readings (Fig.…”

Pendrin stimulates a chloride absorption pathway to increase CFTR‐mediated chloride secretion from Cystic Fibrosis airway epithelia

“…An interesting intersect with the concept of properly balancing pendrin function relates to our finding of pendrin downregulation in CF epithelia. This observation differs from a recent publication which instead reported an upregulation of pendrin 36 . The discrepancy could arise from differences in culture conditions, but might also arise from tissue donor differences.…”

“…siRNA knockdown of pendrin mRNA or inhibition of pendrin activity with niflumic acid blocked this interleukin‐stimulated increase in CFTR current. These observations suggested functional coupling between pendrin and CFTR; this coupling has also been suggested by another recent publication 36 …”

“…However, pendrin is also capable of exchanging bicarbonate for chloride 35 . A recent study identified pendrin as a potential modifier of CFTR function 36 . We hypothesized that pendrin expressed in the airway might increase epithelium Cl − secretion through CFTR by increasing basolateral Cl − absorption.…”

Combined Antioxidant, Anti-inflammaging and Mesenchymal Stem Cell Treatment: A Possible Therapeutic Direction in Elderly Patients with Chronic Obstructive Pulmonary Disease

“…CFTR interacts with pendrin, and the R region of CFTR is phosphorylated by PKA to bind to pendrin's STAS (sulfate transporter and anti-sigma factor antagonist domain), which activates pendrin [36][37][38]. A recent study showed that pendrin mediates bicarbonate secretion and enhances CFTR function in airway surface epithelia [39]. Whether pendrin is synergistic with CFTR transport of GSH is still unclear.…”