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01-12-2010 | Original Article

Acid Suppression by Proton Pump Inhibitors Enhances Aquaporin-4 and KCNQ1 Expression in Gastric Fundic Parietal Cells in Mouse

Authors: Juntaro Matsuzaki, Hidekazu Suzuki, Yuriko Minegishi, Etsuko Sugai, Hitoshi Tsugawa, Masato Yasui, Toshifumi Hibi

Published in: Digestive Diseases and Sciences | Issue 12/2010

Abstract

Background

The widespread use of proton pump inhibitors (PPIs) is known to cause sporadic gastric fundic gland polyps (FGPs). Altered expression and localization of the water or ion transport proteins might contribute to the excess fluid secretion into the cystic lumen for the development of FGPs.

Aims

We investigated the alteration of the murine gastric fundic mucosa after PPI treatment, and examined the expression of water channel aquaporin-4 (AQP4) and potassium channel KCNQ1, which are expressed only in the parietal cells in the gastric mucosa.

Methods

Male 5-week-old C57BL/6J mice were administered lansoprazole (LPZ) by subcutaneous injection for 8 weeks. The expression of AQP4 and KCNQ1 were investigated by Western blotting, quantitative RT-PCR, and immunohistochemistry. The expression of mucin-6 (Muc6), pepsinogen, and sonic hedgehog (Shh) were also investigated as mucosal cell lineage markers.

Results

Gastric mucosal hyperplasia with multiple cystic dilatations, exhibiting similar histological findings to the FGPs, was observed in the LPZ-treated mice. An increase in the number of AQP4-positive parietal cells and KCNQ1-positive parietal cells was observed. The extension of the distribution of AQP4-positive cells toward the surface of the fundic glands was also observed. The expression levels of AQP4 mRNA and protein were significantly enhanced. The expression of KCNQ1 mRNA was correlated with that of AQP4 mRNA in the LPZ-treated mice. Mucous neck-to-zymogenic cell lineage differentiation was delayed in association with decreased expression of Shh in the LPZ-treated mice.

Conclusions

PPI administration increased the number of parietal cells with enhanced expression of AQP4 and KCNQ1.

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Suzuki H, Hibi T. Novel effects other than antisecretory action and off-label use of proton pump inhibitors. Expert Opin Pharmacother. 2005;6:59–67.CrossRefPubMed

Freeman HJ. Proton pump inhibitors and an emerging epidemic of gastric fundic gland polyposis. World J Gastroenterol. 2008;14:1318–1320.CrossRefPubMed

Jalving M, Koornstra JJ, Wesseling J, et al. Increased risk of fundic gland polyps during long-term proton pump inhibitor therapy. Aliment Pharmacol Ther. 2006;24:1341–1348.CrossRefPubMed

Abraham SC, Nobukawa B, Giardiello FM, Hamilton SR, Wu TT. Sporadic fundic gland polyps: common gastric polyps arising through activating mutations in the beta-catenin gene. Am J Pathol. 2001;158:1005–1010.PubMed

Carmack SW, Genta RM, Schuler CM, Saboorian MH. The current spectrum of gastric polyps: a 1-year national study of over 120,000 patients. Am J Gastroenterol. 2009;104:1524–1532.CrossRefPubMed

Genta RM, Schuler CM, Robiou CI, Lash RH. No association between gastric fundic gland polyps and gastrointestinal neoplasia in a study of over 100,000 patients. Clin Gastroenterol Hepatol. 2009;7:849–854.CrossRefPubMed

Lee RG, Burt RW. The histopathology of fundic gland polyps of the stomach. Am J Clin Pathol. 1986;86:498–503.PubMed

Weston BR, Helper DJ, Rex DK. Positive predictive value of endoscopic features deemed typical of gastric fundic gland polyps. J Clin Gastroenterol. 2003;36:399–402.CrossRefPubMed

Ishibashi K, Hara S, Kondo S. Aquaporin water channels in mammals. Clin Exp Nephrol. 2009;13:107–117.CrossRefPubMed

10.

Borgnia M, Nielsen S, Engel A, Agre P. Cellular and molecular biology of the aquaporin water channels. Annu Rev Biochem. 1999;68:425–458.CrossRefPubMed

11.

Ishibashi K, Kuwahara M, Sasaki S. Molecular biology of aquaporins. Rev Physiol Biochem Pharmacol. 2000;141:1–32.CrossRefPubMed

12.

Wang KS, Komar AR, Ma T, et al. Gastric acid secretion in aquaporin-4 knockout mice. Am J Physiol Gastrointest Liver Physiol. 2000;279:G448–G453.PubMed

13.

Xu H, Zhang Y, Wei W, Shen L, Wu W. Differential expression of aquaporin-4 in human gastric normal and cancer tissues. Gastroenterol Clin Biol. 2009;33:72–76.CrossRefPubMed

14.

Lambrecht NW, Yakubov I, Scott D, Sachs G. Identification of the K efflux channel coupled to the gastric H-K-ATPase during acid secretion. Physiol Genomics. 2005;21:81–91.CrossRefPubMed

15.

Dedek K, Waldegger S. Colocalization of KCNQ1/KCNE channel subunits in the mouse gastrointestinal tract. Pflugers Arch. 2001;442:896–902.CrossRefPubMed

16.

Grahammer F, Herling AW, Lang HJ, et al. The cardiac K⁺ channel KCNQ1 is essential for gastric acid secretion. Gastroenterology. 2001;120:1363–1371.CrossRefPubMed

17.

Heitzmann D, Grahammer F, von Hahn T, et al. Heteromeric KCNE2/KCNQ1 potassium channels in the luminal membrane of gastric parietal cells. J Physiol. 2004;561:547–557.CrossRefPubMed

18.

Pan Q, Ma J, Zhou Q, et al. KCNQ1 loss-of-function mutation impairs gastric acid secretion in mice. Mol Biol Rep. 2009;37:1329–1333.CrossRefPubMed

19.

Lee MP, Ravenel JD, Hu RJ, et al. Targeted disruption of the Kvlqt1 gene causes deafness and gastric hyperplasia in mice. J Clin Invest. 2000;106:1447–1455.CrossRefPubMed

20.

Roepke TK, Anantharam A, Kirchhoff P, et al. The KCNE2 potassium channel ancillary subunit is essential for gastric acid secretion. J Biol Chem. 2006;281:23740–23747.CrossRefPubMed

21.

Vallon V, Grahammer F, Volkl H, et al. KCNQ1-dependent transport in renal and gastrointestinal epithelia. Proc Natl Acad Sci USA. 2005;102:17864–17869.CrossRefPubMed

22.

Masaoka T, Suzuki H, Hibi T. Gastric epithelial cell modality and proton pump inhibitor. J Clin Biochem Nutr. 2008;42:191–196.CrossRefPubMed

23.

Mears JM, Kaplan B. Proton pump inhibitors: new drugs and indications. Am Fam Physician. 1996;53:285–292.PubMed

24.

Chen D, Zhao CM, Hakanson R, et al. Altered control of gastric acid secretion in gastrin-cholecystokinin double mutant mice. Gastroenterology. 2004;126:476–487.CrossRefPubMed

25.

Jain RN, Brunkan CS, Chew CS, Samuelson LC. Gene expression profiling of gastrin target genes in parietal cells. Physiol Genomics. 2006;24:124–132.PubMed

26.

Hagiwara T, Mukaisho K, Ling ZQ, et al. Rebamipide contributes to reducing adverse effects of long-term administration of omeprazole in rats. Dig Dis Sci. 2007;52:988–994.CrossRefPubMed

27.

Suzuki H, Minegishi Y, Nomoto Y, et al. Down-regulation of a morphogen (sonic hedgehog) gradient in the gastric epithelium of Helicobacter pylori-infected Mongolian gerbils. J Pathol. 2005;206:186–197.CrossRefPubMed

28.

Nishizawa T, Suzuki H, Nakagawa I, et al. Early Helicobacter pylori eradication restores sonic hedgehog expression in the gastric mucosa of Mongolian gerbils. Digestion. 2009;79:99–108.CrossRefPubMed

29.

Minegishi Y, Suzuki H, Arakawa M, et al. Reduced Shh expression in TFF2-overexpressing lesions of the gastric fundus under hypochlorhydric conditions. J Pathol. 2007;213:161–169.CrossRefPubMed

30.

Houghton J, Stoicov C, Nomura S, et al. Gastric cancer originating from bone marrow-derived cells. Science. 2004;306:1568–1571.CrossRefPubMed

31.

van den Brink GR, Hardwick JC, Tytgat GN, et al. Sonic hedgehog regulates gastric gland morphogenesis in man and mouse. Gastroenterology. 2001;121:317–328.CrossRefPubMed

32.

Xiao C, Ogle SA, Schumacher MA, et al. Loss of parietal cell expression of sonic hedgehog induces hypergastrinemia and hyperproliferation of surface mucous cells. Gastroenterology. 2010;138:550–561.CrossRefPubMed

33.

Matsuzaki T, Tajika Y, Ablimit A, et al. Aquaporins in the digestive system. Med Electron Microsc. 2004;37:71–80.CrossRefPubMed

34.

Heitzmann D, Warth R. No potassium, no acid: K⁺ channels and gastric acid secretion. Physiology (Bethesda). 2007;22:335–341.

35.

Karam SM, Leblond CP. Dynamics of epithelial cells in the corpus of the mouse stomach. III. Inward migration of neck cells followed by progressive transformation into zymogenic cells. Anat Rec. 1993;236:297–313.CrossRefPubMed

36.

Nozaki K, Weis V, Wang TC, Falus A, Goldenring JR. Altered gastric chief cell lineage differentiation in histamine-deficient mice. Am J Physiol Gastrointest Liver Physiol. 2009;296:G1211–G1220.CrossRefPubMed

37.

Nagata A, Ito M, Iwata N, et al. G protein-coupled cholecystokinin-B/gastrin receptors are responsible for physiological cell growth of the stomach mucosa in vivo. Proc Natl Acad Sci USA. 1996;93:11825–11830.CrossRefPubMed

38.

Larsson H, Carlsson E, Mattsson H, et al. Plasma gastrin and gastric enterochromaffinlike cell activation and proliferation. Studies with omeprazole and ranitidine in intact and antrectomized rats. Gastroenterology. 1986;90:391–399.PubMed

39.

Fukushima Y, Shindo T, Anai M, et al. Structural and functional characterization of gastric mucosa and central nervous system in histamine H2 receptor-null mice. Eur J Pharmacol. 2003;468:47–58.CrossRefPubMed

40.

Ogawa T, Maeda K, Tonai S, et al. Utilization of knockout mice to examine the potential role of gastric histamine H2-receptors in Menetrier’s disease. J Pharmacol Sci. 2003;91:61–70.CrossRefPubMed

41.

Takagi H, Jhappan C, Sharp R, Merlino G. Hypertrophic gastropathy resembling Menetrier’s disease in transgenic mice overexpressing transforming growth factor alpha in the stomach. J Clin Invest. 1992;90:1161–1167.CrossRefPubMed

42.

Merchant JL, Demediuk B, Brand SJ. A GC-rich element confers epidermal growth factor responsiveness to transcription from the gastrin promoter. Mol Cell Biol. 1991;11:2686–2696.PubMed

43.

Zavros Y, Rieder G, Ferguson A, Samuelson LC, Merchant JL. Genetic or chemical hypochlorhydria is associated with inflammation that modulates parietal and G-cell populations in mice. Gastroenterology. 2002;122:119–133.CrossRefPubMed

44.

Jain RN, Samuelson LC. Differentiation of the gastric mucosa. II. Role of gastrin in gastric epithelial cell proliferation and maturation. Am J Physiol Gastrointest Liver Physiol. 2006;291:G762–G765.CrossRefPubMed

45.

Karam SM, Straiton T, Hassan WM, Leblond CP. Defining epithelial cell progenitors in the human oxyntic mucosa. Stem Cells. 2003;21:322–336.CrossRefPubMed

46.

Shao JS, Schepp W, Alpers DH. Expression of intrinsic factor and pepsinogen in the rat stomach identifies a subset of parietal cells. Am J Physiol. 1998;274:G62–G70.PubMed

47.

Babaei A, Bhargava V, Aalam S, Scadeng M, Mittal RK. Effect of proton pump inhibition on the gastric volume: assessed by magnetic resonance imaging. Aliment Pharmacol Ther. 2009;29:863–870.CrossRefPubMed

48.

Hocker M, Zhang Z, Merchant JL, Wang TC. Gastrin regulates the human histidine decarboxylase promoter through an AP-1-dependent mechanism. Am J Physiol. 1997;272:G822–G830.PubMed

49.

Zavros Y, Waghray M, Tessier A, et al. Reduced pepsin A processing of sonic hedgehog in parietal cells precedes gastric atrophy and transformation. J Biol Chem. 2007;282:33265–33274.CrossRefPubMed

50.

Burkitt MD, Varro A, Pritchard DM. Importance of gastrin in the pathogenesis and treatment of gastric tumors. World J Gastroenterol. 2009;15:1–16.CrossRefPubMed

Title: Acid Suppression by Proton Pump Inhibitors Enhances Aquaporin-4 and KCNQ1 Expression in Gastric Fundic Parietal Cells in Mouse
Authors: Juntaro Matsuzaki
Hidekazu Suzuki
Yuriko Minegishi
Etsuko Sugai
Hitoshi Tsugawa
Masato Yasui
Toshifumi Hibi
Publication date: 01-12-2010
Publisher: Springer US
Published in: Digestive Diseases and Sciences / Issue 12/2010
Print ISSN: 0163-2116
Electronic ISSN: 1573-2568
DOI: https://doi.org/10.1007/s10620-010-1167-8

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Acid Suppression by Proton Pump Inhibitors Enhances Aquaporin-4 and KCNQ1 Expression in Gastric Fundic Parietal Cells in Mouse

Abstract

Background

Aims

Methods

Results

Conclusions

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