Impaired gastric acid secretion in mice with a targeted disruption of the NHE4 Na+/H+ exchanger.

Abstract

The NHE4 Na+/H+ exchanger is abundantly expressed on the basolateral membrane of gastric parietal cells. To test the hypothesis that it is required for normal acid secretion, NHE4-null mutant (NHE4-/-) mice were prepared by targeted disruption of the NHE4 (Slc9a4) gene. NHE4-/- mice survived and appeared outwardly normal. Analysis of stomach contents revealed that NHE4-/- mice were hypochlorhydric. The reduction in acid secretion was similar in 18-day-old, 9-week-old, and 6-month-old mice, indicating that the hypochlorhydria phenotype did not progress over time, as was observed in mice lacking the NHE2 Na+/H+ exchanger. Histological abnormalities were observed in the gastric mucosa of 9-week-old NHE4-/- mice, including sharply reduced numbers of parietal cells, a loss of mature chief cells, increased numbers of mucous and undifferentiated cells, and an increase in the number of necrotic and apoptotic cells. NHE4-/- parietal cells exhibited limited development of canalicular membranes and a virtual absence of tubulovesicles, and some of the microvilli had centrally bundled actin. We conclude that NHE4, which may normally be coupled with the AE2 Cl-/HCO3- exchanger, is important for normal levels of gastric acid secretion, gastric epithelial cell differentiation, and development of secretory canalicular and tubulovesicular membranes.

• Authors: Lara R Gawenis, Jeannette M Greeb, Vikram Prasad, Christina Grisham, L Philip Sanford, Thomas Doetschman, Anastasia Andringa, Marian L Miller, Gary E Shull
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 280 Issue 13 Pg. 12781-9 (Apr 01 2005) ISSN: 0021-9258 [Print] United States
• PMID: 15684419 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• DNA, Complementary
• Gastrins
• RNA, Messenger
• Slc9a4 protein, mouse
• Sodium-Hydrogen Exchangers
• RNA

Topics

• Achlorhydria (pathology)
• Alleles
• Alternative Splicing
• Animals
• Apoptosis
• Blotting, Northern
• Blotting, Western
• Cell Differentiation
• DNA, Complementary (metabolism)
• Dose-Response Relationship, Drug
• Exons
• Gastric Acid (metabolism)
• Gastrins (metabolism)
• Hydrogen-Ion Concentration
• Immunoblotting
• In Situ Nick-End Labeling
• Mice
• Mice, Transgenic
• Microscopy, Electron
• Models, Biological
• Models, Genetic
• Mutation
• Necrosis
• Parietal Cells, Gastric (cytology, ultrastructure)
• Phenotype
• RNA (metabolism)
• RNA, Messenger (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Sodium-Hydrogen Exchangers (metabolism, physiology)
• Time Factors