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Genetic ablation of carbonic anhydrase IX disrupts gastric barrier function via claudin‐18 downregulation and acid backflux
AIM: This study aimed to explore the molecular mechanisms for the parietal cell loss and fundic hyperplasia observed in gastric mucosa of mice lacking the carbonic anhydrase 9 (CAIX). METHODS: We assessed the ability of CAIX‐knockout and WT gastric surface epithelial cells to withstand a luminal aci...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5901031/ https://www.ncbi.nlm.nih.gov/pubmed/28748627 http://dx.doi.org/10.1111/apha.12923 |
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author | Li, T. Liu, X. Riederer, B. Nikolovska, K. Singh, A. K. Mäkelä, K. A. Seidler, A. Liu, Y. Gros, G. Bartels, H. Herzig, K. H. Seidler, U. |
author_facet | Li, T. Liu, X. Riederer, B. Nikolovska, K. Singh, A. K. Mäkelä, K. A. Seidler, A. Liu, Y. Gros, G. Bartels, H. Herzig, K. H. Seidler, U. |
author_sort | Li, T. |
collection | PubMed |
description | AIM: This study aimed to explore the molecular mechanisms for the parietal cell loss and fundic hyperplasia observed in gastric mucosa of mice lacking the carbonic anhydrase 9 (CAIX). METHODS: We assessed the ability of CAIX‐knockout and WT gastric surface epithelial cells to withstand a luminal acid load by measuring the pH (i) of exteriorized gastric mucosa in vivo using two‐photon confocal laser scanning microscopy. Cytokines and claudin‐18A2 expression was analysed by RT‐PCR. RESULTS: CAIX‐knockout gastric surface epithelial cells showed significantly faster pH (i) decline after luminal acid load compared to WT. Increased gastric mucosal IL‐1β and iNOS, but decreased claudin‐18A2 expression (which confer acid resistance) was observed shortly after weaning, prior to the loss of parietal and chief cells. At birth, neither inflammatory cytokines nor claudin‐18 expression were altered between CAIX and WT gastric mucosa. The gradual loss of acid secretory capacity was paralleled by an increase in serum gastrin, IL‐11 and foveolar hyperplasia. Mild chronic proton pump inhibition from the time of weaning did not prevent the claudin‐18 decrease nor the increase in inflammatory markers at 1 month of age, except for IL‐1β. However, the treatment reduced the parietal cell loss in CAIX‐KO mice in the subsequent months. CONCLUSIONS: We propose that CAIX converts protons that either backflux or are extruded from the cells rapidly to CO (2) and H(2)O, contributing to tight junction protection and gastric epithelial pH (i) regulation. Lack of CAIX results in persistent acid backflux via claudin‐18 downregulation, causing loss of parietal cells, hypergastrinaemia and foveolar hyperplasia. |
format | Online Article Text |
id | pubmed-5901031 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-59010312018-04-24 Genetic ablation of carbonic anhydrase IX disrupts gastric barrier function via claudin‐18 downregulation and acid backflux Li, T. Liu, X. Riederer, B. Nikolovska, K. Singh, A. K. Mäkelä, K. A. Seidler, A. Liu, Y. Gros, G. Bartels, H. Herzig, K. H. Seidler, U. Acta Physiol (Oxf) Gastrointestinal Physiology AIM: This study aimed to explore the molecular mechanisms for the parietal cell loss and fundic hyperplasia observed in gastric mucosa of mice lacking the carbonic anhydrase 9 (CAIX). METHODS: We assessed the ability of CAIX‐knockout and WT gastric surface epithelial cells to withstand a luminal acid load by measuring the pH (i) of exteriorized gastric mucosa in vivo using two‐photon confocal laser scanning microscopy. Cytokines and claudin‐18A2 expression was analysed by RT‐PCR. RESULTS: CAIX‐knockout gastric surface epithelial cells showed significantly faster pH (i) decline after luminal acid load compared to WT. Increased gastric mucosal IL‐1β and iNOS, but decreased claudin‐18A2 expression (which confer acid resistance) was observed shortly after weaning, prior to the loss of parietal and chief cells. At birth, neither inflammatory cytokines nor claudin‐18 expression were altered between CAIX and WT gastric mucosa. The gradual loss of acid secretory capacity was paralleled by an increase in serum gastrin, IL‐11 and foveolar hyperplasia. Mild chronic proton pump inhibition from the time of weaning did not prevent the claudin‐18 decrease nor the increase in inflammatory markers at 1 month of age, except for IL‐1β. However, the treatment reduced the parietal cell loss in CAIX‐KO mice in the subsequent months. CONCLUSIONS: We propose that CAIX converts protons that either backflux or are extruded from the cells rapidly to CO (2) and H(2)O, contributing to tight junction protection and gastric epithelial pH (i) regulation. Lack of CAIX results in persistent acid backflux via claudin‐18 downregulation, causing loss of parietal cells, hypergastrinaemia and foveolar hyperplasia. John Wiley and Sons Inc. 2017-10-19 2018-04 /pmc/articles/PMC5901031/ /pubmed/28748627 http://dx.doi.org/10.1111/apha.12923 Text en © 2017 The Authors. Acta Physiologica Published by John Wiley & Sons Ltd on behalf of Scandinavian Physiological Society This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Gastrointestinal Physiology Li, T. Liu, X. Riederer, B. Nikolovska, K. Singh, A. K. Mäkelä, K. A. Seidler, A. Liu, Y. Gros, G. Bartels, H. Herzig, K. H. Seidler, U. Genetic ablation of carbonic anhydrase IX disrupts gastric barrier function via claudin‐18 downregulation and acid backflux |
title | Genetic ablation of carbonic anhydrase IX disrupts gastric barrier function via claudin‐18 downregulation and acid backflux |
title_full | Genetic ablation of carbonic anhydrase IX disrupts gastric barrier function via claudin‐18 downregulation and acid backflux |
title_fullStr | Genetic ablation of carbonic anhydrase IX disrupts gastric barrier function via claudin‐18 downregulation and acid backflux |
title_full_unstemmed | Genetic ablation of carbonic anhydrase IX disrupts gastric barrier function via claudin‐18 downregulation and acid backflux |
title_short | Genetic ablation of carbonic anhydrase IX disrupts gastric barrier function via claudin‐18 downregulation and acid backflux |
title_sort | genetic ablation of carbonic anhydrase ix disrupts gastric barrier function via claudin‐18 downregulation and acid backflux |
topic | Gastrointestinal Physiology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5901031/ https://www.ncbi.nlm.nih.gov/pubmed/28748627 http://dx.doi.org/10.1111/apha.12923 |
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