Hip1r is expressed in gastric parietal cells and is required for tubulovesicle formation and cell survival in mice
Renu N. Jain, … , Catherine S. Chew, Linda C. Samuelson
Renu N. Jain, … , Catherine S. Chew, Linda C. Samuelson
Published June 5, 2008
Citation Information: J Clin Invest. 2008;118(7):2459-2470. https://doi.org/10.1172/JCI33569.
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Research Article Cell biology

Hip1r is expressed in gastric parietal cells and is required for tubulovesicle formation and cell survival in mice

Abstract

Huntingtin interacting protein 1 related (Hip1r) is an F-actin– and clathrin-binding protein involved in vesicular trafficking. In this study, we demonstrate that Hip1r is abundantly expressed in the gastric parietal cell, predominantly localizing with F-actin to canalicular membranes. Hip1r may provide a critical function in vivo, as demonstrated by extensive changes to parietal cells and the gastric epithelium in Hip1r-deficient mice. Electron microscopy revealed abnormal apical canalicular membranes and loss of tubulovesicles in mutant parietal cells, suggesting that Hip1r is necessary for the normal trafficking of these secretory membranes. Accordingly, acid secretory dynamics were altered in mutant parietal cells, with enhanced activation and acid trapping, as measured in isolated gastric glands. At the whole-organ level, gastric acidity was reduced in Hip1r-deficient mice, and the gastric mucosa was grossly transformed, with fewer parietal cells due to enhanced apoptotic cell death and glandular hypertrophy associated with cellular transformation. Hip1r-deficient mice had increased expression of the gastric growth factor gastrin, and mice mutant for both gastrin and Hip1r exhibited normalization of both proliferation and gland height. Taken together, these studies demonstrate that Hip1r plays a significant role in gastric physiology, mucosal architecture, and secretory membrane dynamics in parietal cells.

Authors

Renu N. Jain, Asma A. Al-Menhali, Theresa M. Keeley, Jianhua Ren, Mohammed El-Zaatari, Xunsheng Chen, Juanita L. Merchant, Theodora S. Ross, Catherine S. Chew, Linda C. Samuelson

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Figure 5

Reduced acid secretion and gross histological changes in Hip1r-deficient mouse stomach.

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Reduced acid secretion and gross histological changes in Hip1r-deficient...
(A) Acid content from the stomachs of 2- to 4-month-old WT and Hip1r-deficient mice. Values (mean ± SEM) were normalized to body wt. Mice were fasted (n = 6 per genotype) or treated with histamine (n = 3 per genotype) to measure basal and stimulated acid contents, respectively. *P < 0.005 versus unstimulated WT. (B–G) Histological analysis of gastric paraffin sections from 2-month-old WT (B, D, and F) and Hip1r-deficient (C, E, and G) mice after H&E staining (B–E) or H+, K+-ATPase immunostaining (F and G). H&E staining revealed a hypertrophic mucosa in Hip1r-deficient mice with cystic structures (C, arrow) and inflammatory cell infiltrates (C, arrowheads). (D and E) Higher-magnification views of boxed regions in B and C, respectively, demonstrate the marked cellular changes in Hip1r-deficient mice, including numerous delaminated cells (E, arrowheads). In comparison to the abundant parietal cells (arrows) in WT mice, only 1 recognizable parietal cell was seen in Hip1r-deficient mice. (F and G) Sections stained for parietal cells with a mAb to the α subunit of H+, K+-ATPase. Insets show higher-magnification images of boxed regions. (H and I) Similar analysis of 3-week-old WT (H) and Hip1r-deficient (I) mice by H+, K+-ATPase immunostaining demonstrated parietal cell abnormalities in young mice. Scale bars: 100 μm (B–I); 20 μm (F–I, insets).