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

Abstract

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 ␣-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 ␣-subunit mRNA and protein, the ␤-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 adult Atp4a؊/؊ mice exhibited metaplasia, which included the presence of ciliated cells. We conclude that ablation of the H,K-ATPase ␣-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.

Transcription of Sonic Hedgehog, a Potential Factor for Gastric Morphogenesis and Gastric Mucosa Maintenance, Is Up-regulated in Acidic Conditions

“…Increased proliferation and cell turnover in this compartment were also described in patients with atrophy (Biasco et al, 1989;Miwa et al, 1997) and in animals treated with the proton pumpinhibitor omeprazole (Kakei et al, 1993(Kakei et al, , 1995. These animals, like the H,K-ATPase knockout mice in previous studies (Scarff et al, 1999;Spicer et al, 2000), showed both achlorhydria and suppressed differentiation of gastric chief cells. Therefore, it might be speculated that gastric acid represents a key factor for gastric morphogenesis.…”

Salivary Acinar Cells from Aquaporin 5-deficient Mice Have Decreased Membrane Water Permeability and Altered Cell Volume Regulation

“…Blood Gas and Electrolyte Analysis-Tail vein blood (50 l) was collected from adult Aqp5 ϩ/ϩ and Aqp5 Ϫ/Ϫ age-and sex-matched littermates (12-16 weeks of age, n ϭ 6 each genotype) and analyzed for gases, electrolytes, and pH as described (19).…”

Kir4.1 Channel Expression Is Essential for Parietal Cell Control of Acid Secretion

“…, demonstrated a totally different situation from that in Kir4.1 Ϫ/Ϫ PCs: instead of secretory membranes, large vacuoles with scant microvilli and very occasional vesicular structures resembling tubulovesicles are seen in Atp4␣-deficient PCs (33). Clearly, the microvilli are long and well defined in Kir4.1 Ϫ/Ϫ secretory membranes.…”