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Pendrin stimulates a chloride absorption pathway to increase CFTR-mediated chloride secretion from Cystic Fibrosis airway epithelia.
Bajko, Jeffrey; Duguid, Mei; Altmann, Steve; Hurlbut, Gregory D; Kaczmarek, J Stefan.
Affiliation
  • Bajko J; Sanofi Framingham MA USA.
  • Duguid M; Sanofi Framingham MA USA.
  • Altmann S; Sanofi Framingham MA USA.
  • Hurlbut GD; Sanofi Framingham MA USA.
  • Kaczmarek JS; Sanofi Framingham MA USA.
FASEB Bioadv ; 2(9): 526-537, 2020 Sep.
Article in En | MEDLINE | ID: mdl-32923987
Cystic Fibrosis (CF), an inherited multi-system disease, is caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) that disrupt its ability to secrete anions from epithelia. Recovery of functional anion secretion may be curative for CF, so different components of the ion transport machinery have become attractive therapeutic targets. Several members of the SLC26 ion transporter family have been linked to epithelial ion flux, some through putative functional interactions with CFTR. Using a small-scale qPCR screen, we confirmed that the anion transporter SLC26A4 (pendrin) is downregulated in CF. Upregulation of pendrin using interleukins IL-4 or IL-13 increased Cl- secretion through CFTR in human bronchial epithelial cell (HBEC) derived epithelia differentiated in vitro and measured in the Ussing Chamber. Inhibition or knockdown of pendrin prevented this increased secretion. Increased CFTR activity was not driven by increases in CFTR protein or upstream regulatory pathway components. When basolateral Cl- absorption through NKCC1 was inhibited, a pendrin-dependent Cl- absorption pathway allowing CFTR to continue secreting Cl- from the epithelium was revealed. Although CFTR is often considered the bottleneck in the transepithelial Cl- transport pathway, these studies indicate that basolateral Cl- permeability becomes limiting as CFTR activity increases. Therefore, an increase of epithelial Cl- absorption via pendrin might have additional therapeutic benefit in combination with CFTR modulators.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Language: En Journal: FASEB Bioadv Year: 2020 Document type: Article Country of publication:

Full text: 1 Collection: 01-internacional Database: MEDLINE Language: En Journal: FASEB Bioadv Year: 2020 Document type: Article Country of publication: