Abnormal functional and morphological regulation of the gastric mucosa in histamine H2 receptor–deficient mice
Takashi Kobayashi, … , Susumu Okabe, Takeshi Watanabe
Takashi Kobayashi, … , Susumu Okabe, Takeshi Watanabe
Published June 15, 2000
Citation Information: J Clin Invest. 2000;105(12):1741-1749. https://doi.org/10.1172/JCI9441.
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Article

Abnormal functional and morphological regulation of the gastric mucosa in histamine H2 receptor–deficient mice

Abstract

To clarify the physiological roles of histamine H2 receptor (H2R), we have generated histamine H2R-deficient mice by gene targeting. Homozygous mutant mice were viable and fertile without apparent abnormalities and, unexpectedly, showed normal basal gastric pH. However, the H2R-deficient mice exhibited a marked hypertrophy with enlarged folds in gastric mucosa and an elevated serum gastrin level. Immunohistochemical analysis revealed increased numbers of parietal and enterochromaffin-like (ECL) cells. Despite this hypertrophy, parietal cells in mutant mice were significantly smaller than in wild-type mice and contained enlarged secretory canaliculi with a lower density of microvilli and few typical tubulovesicles in the narrow cytoplasm. Induction of gastric acid secretion by histamine or gastrin was completely abolished in the mutant mice, but carbachol still induced acid secretion. The present study clearly demonstrates that H2R-mediated signal(s) are required for cellular homeostasis of the gastric mucosa and normally formed secretory membranes in parietal cells. Moreover, impaired acid secretion due to the absence of H2R could be overcome by the signals from cholinergic receptors.

Authors

Takashi Kobayashi, Shunsuke Tonai, Yasunobu Ishihara, Ritsuko Koga, Susumu Okabe, Takeshi Watanabe

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Figure 1

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Targeted deletion of the mouse H2R gene. (a) A diagram of the targeting ...
Targeted deletion of the mouse H2R gene. (a) A diagram of the targeting vector (middle) designed to replace the XbaI–HindIII fragment containing the H2R exon in the wild allele (top) with a pGK-neo cassette. The predicted mutant allele (bottom) generated by homologous recombination is also shown. A neomycin resistance gene (neor) and a herpes simplex virus-thymidine kinase gene (hsv-tk) inserted in reverse orientation are indicated as upside down. (b) Southern blot analysis of the homologous recombination. The genomic DNAs from a recombinant ES clone (left lane) and F2 offspring obtained by a heterozygous intercrossing were digested with EcoRI and SalI and hybridized with the 3′ external probe. Each band corresponding to the wild-type allele (16 kb) and mutant allele (3.5 kb) is indicated. (c) The expression of H2R mRNA in stomach (St) and brain (Br). Ethidium bromide staining of RT-PCR products corresponding to the H2R (top) and endogenous β-actin (bottom). The cDNA was synthesized from DNaseI-pretreated total RNA in the presence (+) or absence (–) of MLV reverse transcriptase (RT). RT-PCR products from the top panel were reconfirmed by Southern blot analysis using a genomic probe (middle). P, PCR products of H2R genomic DNA and β-actin cDNA as a positive control; N, no template control for PCR.