Stomachs of Mice Lacking the Gastric H,K-ATPase α-Subunit Have Achlorhydria, Abnormal Parietal Cells, and Ciliated Metaplasia

The H,K-ATPase of the gastric parietal cell is the most critical component of the ion transport system mediating acid secretion in the stomach. To study the requirement of this enzyme in the development, maintenance, and function of the gastric mucosa, we used gene targeting to prepare mice lacking...

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Bibliographic Details
Published in:The Journal of biological chemistry 2000-07, Vol.275 (28), p.21555-21565
Main Authors: Spicer, Zachary, Miller, Marian L., Andringa, Anastasia, Riddle, Tara M., Duffy, John J., Doetschman, Thomas, Shull, Gary E.
Format: Article
Language:English
Subjects:
Achlorhydria - blood
Achlorhydria - genetics
Achlorhydria - pathology
Animals
Atp4a gene
Cilia - pathology
Electrolytes - blood
Gastric Acid - metabolism
Gastric Mucosa - pathology
Gastric Mucosa - ultrastructure
H(+)-K(+)-Exchanging ATPase - deficiency
H(+)-K(+)-Exchanging ATPase - genetics
H(+)-K(+)-Exchanging ATPase - metabolism
Metaplasia
Mice
Mice, Knockout
Parietal Cells, Gastric - pathology
Parietal Cells, Gastric - ultrastructure
Pepsinogen A - analysis
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Summary:The H,K-ATPase of the gastric parietal cell is the most critical component of the ion transport system mediating acid secretion in the stomach. To study the requirement of this enzyme in the development, maintenance, and function of the gastric mucosa, we used gene targeting to prepare mice lacking the α-subunit. Homozygous mutant (Atp4a−/−) mice appeared healthy and exhibited normal systemic electrolyte and acid-base status but were achlorhydric and hypergastrinemic. Immunocytochemical, histological, and ultrastructural analyses of Atp4a−/−stomachs revealed the presence of chief cells, demonstrating that the lack of acid secretion does not interfere with their differentiation. Parietal cells were also present in normal numbers, and despite the absence of α-subunit mRNA and protein, the β-subunit was expressed. However, Atp4a−/− parietal cells had dilated canaliculi and lacked typical canalicular microvilli and tubulovesicles, and subsets of these cells contained abnormal mitochondria and/or massive glycogen stores. Stomachs of adultAtp4a−/− mice exhibited metaplasia, which included the presence of ciliated cells. We conclude that ablation of the H,K-ATPase α-subunit causes achlorhydria and hypergastrinemia, severe perturbations in the secretory membranes of the parietal cell, and metaplasia of the gastric mucosa; however, the absence of the pump appears not to perturb parietal cell viability or chief cell differentiation.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M001558200