Regenerating gene protein may mediate gastric mucosal proliferation induced by hypergastrinemia in rats

doi:10.1016/S0016-5085(98)70027-7

Gastroenterology

Volume 115, Issue 6, December 1998, Pages 1483-1493

https://doi.org/10.1016/S0016-5085(98)70027-7 Get rights and content

Abstract

Background & Aims: Regenerating gene (Reg) has been isolated from rat regenerating pancreatic islets, and Reg protein is mitogenic to islet cells. We have recently shown that Reg gene and Reg protein are expressed in gastric enterochromaffin-like (ECL) cells. This study aimed to clarify whether gastrin enhances Reg protein production in ECL cells and whether Reg protein is mitogenic to gastric mucosal cells. Methods: Reg gene expression in response to acute and chronic hypergastrinemia was investigated in rats. Immunohistochemical studies, Northern blotting, and in situ hybridization were performed to investigate the expression of Reg protein and Reg gene. The direct effect of gastrin on Reg gene expression was investigated using isolated ECL cells, and the trophic effect of Reg protein on cultured gastric epithelial cells was assessed by [³H]thymidine uptake. Results: Both chronic hypergastrinemia and short-term gastrin administration stimulated Reg gene expression and Reg protein production in fundic mucosa. Reg gene expression was also augmented in isolated ECL cells after incubation with rat gastrin. Reg protein was mitogenic to cultured rat gastric epithelial cells. Conclusions: Gastrin stimulates the production of Reg protein in gastric ECL cells, which may be involved in the gastrin-induced gastric mucosal cell growth.

GASTROENTEROLOGY 1998;115:1483-1493

Section snippets

Effect of chronic hypergastrinemia on rat stomach

Seven-week-old male Sprague–Dawley rats (Clea Japan, Tokyo, Japan) were divided into four groups. The first group received the vehicle, 0.5% sodium carboxymethyl cellulose, pH 7.6, via a gastric tube once a day for 28 days. The second group was treated with lansoprazole (Takeda, Osaka, Japan) diluted in the vehicle, at a dose of 30 mg/kg body wt once a day for 28 days. This dose has been shown to induce complete achlorhydria in adult rats.¹⁶ The third group was treated with both the gastrin

Effects of long-term administration of lansoprazole and/or the gastrin receptor antagonist on rat stomach

In rats given lansoprazole or AG-041R, the serum gastrin level was increased significantly (P < 0.01 and P < 0.05, respectively, vs. control). Concomitant administration of lansoprazole and AG-041R further increased the serum gastrin level (P < 0.01) (Table 1).

The thickness of the fundic mucosa in control rats was 509 ± 4 μm and was significantly increased by lansoprazole administration (P < 0.01). The effect of lansoprazole on the mucosal thickness was completely abolished by concomitant

Discussion

In the present study, we have clearly shown that chronic hypergastrinemia induced by lansoprazole enhanced the proliferation of gastric mucosal cells, particularly in the neck zone, and increased the thickness of the fundic mucosa in rats. This trophic action was completely abolished by a potent gastrin receptor antagonist, AG-041R. These data agree well with the results of several previous in vivo studies showing that chronic hypergastrinemia exerts a trophic action on the gastric mucosa6, 7,

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Unique membranous gastrin receptor expression of parietal cells and its distribution pattern in the gastric oxyntic mucosa and fundic gland polyps
2022, Human Pathology
Citation Excerpt :
Gastrin stimulates secretion of gastric acid, either directly by binding to the GR of parietal cells or indirectly by enhancing histamine release from ECL cells [5,6]. Furthermore, the gastrin-GR system promotes the proliferation of ECL cells by activating the MAP kinase pathway [5,7,8] and stimulates the gastric mucosal epithelial growth by releasing several growth factors from ECL and parietal cells [9–11]. GR has also been reported to be expressed in several human carcinomas and tumors including those of gastric origin [12,13].
The aim of this study was to clarify the correlation between gastrin receptor (GR) expression in the gastric oxyntic mucosa and fundic gland polyps (FGPs) and the histological and immunohistochemical findings of the mucosa as well as the history of proton pump inhibitor (PPI) administration. The unique membranous linear positivity of GR in parietal cells was reproducibly observed by immunohistochemistry, which was also validated by immunofluorescence. Further histological and immunohistochemical examination of 34 oxyntic mucosae and 43 FGPs revealed the following: 1) parietal cells (PCs) with membranous linear GR expression (mGR) were observed to be limited to the isthmus-neck region in the normal state; 2) appearance of PCs with mGR in the deep oxyntic gland regions was significantly related to the PPI medication history; 3) PCs with mGR were more frequently observed in the deep oxyntic gland regions when the oxyntic mucosa showed derangement of mucosal component cell compartmentalization revealed by MUC5AC and MUC6 immunohistochemistry, which was also significantly related to the PPI use; and 4) PCs with intense membranous linear positivity of GR were observed to be diffusely distributed in all of the cases of FGPs. In conclusion, the distribution of unique GR membranous linear expression in PCs of the oxyntic mucosa under PPI medication and FGPs could reflect the pathologic mucosal state characterized by derangement of the compartmentalization of mucosal component cells, which could be another basis for evaluating physiologic and/or pathophysiologic conditions of the gastric mucosa.
Protective and anti-inflammatory role of REG1A in inflammatory bowel disease induced by JAK/STAT3 signaling axis
2021, International Immunopharmacology
Regenerating islet-derived protein 1-alpha (REG1A) was abnormally upregulated in a series of gastrointestinal inflammatory disorders. However, the potential biological function and underlying regulatory mechanisms of the increased REG1A in inflammatory bowel disease (IBD) pathogenesis remain to be fully elucidated. In this study, we uncovered that REG1A was substantially increased in the inflamed colorectal tissues of IBD patients. And the aberrantly expressed REG1A in intestinal epithelial cells (IEC) prominently inhibited inflammatory responses, promoted cell proliferation and suppressed epithelial apoptosis. Mechanically, IL-6 and IL-22 markedly activated REG1A transcription through triggering JAK/STAT3 signaling pathway. In addition, overexpression of REG1A in mice by systematic delivery of REG1A lentivirus remarkably alleviated DSS-induced inflammatory injury and maintained the integrity of intestinal mucosal barrier. Taken together, our data demonstrated that the novel proliferative factor REG1A controlled by IL-6/IL-22-JAK-STAT3 signaling may provide a promising therapeutic target for patients with IBD.
Stomach Hormones
2020, Hormonal Signaling in Biology and Medicine: Comprehensive Modern Endocrinology
The hormone concept, based upon studies in the upper gastrointestinal tract, was developed more than 100 years ago. The regulation of gastric acid secretion has been a central subject throughout the last century. Leaps were made in the 1960s, with isolation and characterization of new hormones, due to improvement in separation of peptides, and not least, due to the development of immunoassays allowing determination of concentrations in the low picomolar range. Slowly, the role of hormones in clinical gastroenterology was realized: first when diagnosing rare tumors originating from hormone-producing cells, and later when characterizing the pathogenesis of duodenal ulcer caused by Helicobacter pylori. The present overview will focus on the two gastric hormones gastrin and ghrelin. Locally active signal substances working via the paracrine route, like somatostatin and histamine, as well as the neuroendocrine cells producing them, are less thoroughly described. Gastrin is central in gastric physiology by controlling and keeping gastric acidity sufficiently low to allow the killing of swallowed microorganisms, via regulation of enterochromaffin-like cell histamine release as well as proliferation. Infection with H. pylori, as well as drug-induced hypoacidity, results in hypergastrinemia, which in the long term may lead to gastric cancer. Thus, gastrin may play an important role in most diseases of the upper gastrointestinal tract. It is possible that other hormones could have a similar pathogenic role in other locations, where we have less knowledge of the physiology.
Stomach Hormones
2019, Hormonal Signaling in Biology and Medicine: Comprehensive Modern Endocrinology
The hormone concept, based upon studies in the upper gastrointestinal tract, was developed more than 100 years ago. The regulation of gastric acid secretion has been a central subject throughout the last century. Leaps were made in the 1960s, with isolation and characterization of new hormones, due to improvement in separation of peptides, and not least, due to the development of immunoassays allowing determination of concentrations in the low picomolar range. Slowly, the role of hormones in clinical gastroenterology was realized: first when diagnosing rare tumors originating from hormone-producing cells, and later when characterizing the pathogenesis of duodenal ulcer caused by Helicobacter pylori. The present overview will focus on the two gastric hormones gastrin and ghrelin. Locally active signal substances working via the paracrine route, like somatostatin and histamine, as well as the neuroendocrine cells producing them, are less thoroughly described. Gastrin is central in gastric physiology by controlling and keeping gastric acidity sufficiently low to allow the killing of swallowed microorganisms, via regulation of enterochromaffin-like cell histamine release as well as proliferation. Infection with H. pylori, as well as drug-induced hypoacidity, results in hypergastrinemia, which in the long term may lead to gastric cancer. Thus, gastrin may play an important role in most diseases of the upper gastrointestinal tract. It is possible that other hormones could have a similar pathogenic role in other locations, where we have less knowledge of the physiology.
Expression of REG family genes in human inflammatory bowel diseases and its regulation
2017, Biochemistry and Biophysics Reports
The pathophysiology of inflammatory bowel disease (IBD) reflects a balance between mucosal injury and reparative mechanisms. Some regenerating gene (Reg) family members have been reported to be expressed in Crohn's disease (CD) and ulcerative colitis (UC) and to be involved as proliferative mucosal factors in IBD. However, expression of all REG family genes in IBD is still unclear. Here, we analyzed expression of all REG family genes (REG Iα, REG Iβ, REG III, HIP/PAP, and REG IV) in biopsy specimens of UC and CD by real-time RT-PCR. REG Iα, REG Iβ, and REG IV genes were overexpressed in CD samples. REG IV gene was also overexpressed in UC samples. We further analyzed the expression mechanisms of REG Iα, REG Iβ, and REG IV genes in human colon cells. The expression of REG Iα was significantly induced by IL-6 or IL-22, and REG Iβ was induced by IL-22. Deletion analyses revealed that three regions (− 220 to − 211, − 179 to − 156, and − 146 to − 130) in REG Iα and the region (− 274 to− 260) in REG Iβ promoter were responsible for the activation by IL-22/IL-6. The promoters contain consensus transcription factor binding sequences for MZF1, RTEF1/TEAD4, and STAT3 in REG Iα, and HLTF/FOXN2F in REG Iβ, respectively. The introduction of siRNAs for MZF1, RTEF1/TEAD4, STAT3, and HLTF/FOXN2F abolished the transcription of REG Iα and REG Iβ. The gene activation mechanisms of REG Iα/REG Iβ may play a role in colon mucosal regeneration in IBD.
REG1B as a predictor of childhood stunting in Bangladesh and Peru1-3
2013, American Journal of Clinical Nutrition
Undernutrition remains a significant problem worldwide, with environmental enteropathy implicated as a contributing factor. An understanding of the pathogenesis and identification of children at risk are critical to the design of more-effective interventions.
The stool regenerating gene 1β (REG1B) protein, which is a putative measure of intestinal injury and repair, was tested as a noninvasive biomarker of future childhood stunting.
A total of 222 children from Bangladesh and 97 children from Peru, who were from impoverished communities, were followed from birth through 24 mo of age with anthropometric measures obtained every 3 mo. Stool REG1B protein concentrations were obtained by using an REG1B polyclonal-polyclonal ELISA at 3 mo of age. We tested for the ability of REG1B to forecast future anthropometric shortfalls, independent of known predictors of undernutrition of family income and baseline height and weight.
In the Bangladesh cohort of 222 children, higher REG1B concentrations at month 3 were significantly and independently associated with a growth shortfall in a linear regression analysis at months 9, 12, 18, 21, and 24 and, in the Peru cohort, at months 12, 15, 18, 21, and 24. With the use of a mixed model for repeated measurements, higher stool REG1B concentrations at 3 mo were also independently predictive of a lower future length-for-age z score through 24 mo of age (Bangladesh P = 0.006; Peru P = 0.058).
The ability of fecal REG1B to predict growth shortfall in independent cohorts of impoverished children from the developing world offers promise as a malnutrition biomarker and supports a role for environmental enteropathy in the pathogenesis of growth shortfall.

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^☆: Address requests for reprints to: Tsutomu Chiba, M.D., Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, 54, Kawaramachi-shogoin, Sakyo-ku, Kyoto 606-01, Japan. Fax: (81) 75-751-4303.

^☆☆: Supported in part by Grants-in-aid for Scientific Research and Cancer Research from the Ministry of Education, Science and Culture, a grant from the Ministry of Health and Welfare, Japan, and from the Japan Society for the Promotion of Science (no. JSPS-RFTF97I00201).

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Alimentary TractRegenerating gene protein may mediate gastric mucosal proliferation induced by hypergastrinemia in rats☆,☆☆

Abstract

Section snippets

Effect of chronic hypergastrinemia on rat stomach

Effects of long-term administration of lansoprazole and/or the gastrin receptor antagonist on rat stomach

Discussion

Gastroenterology

Gastroenterology

Biochem Biophys Res Commun

J Biol Chem

J Biol Chem

J Biol Chem

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

FEBS Lett

Gastroenterology

J Biol Chem

Gastroenterology

Dynamics of epithelial cells in the corpus of the mouse stomach

Anat Rec

Tritiated thymidine autoradiographic study of cellular migration in the gastric gland of the golden hamster

Cell Tissue Res

Alimentary Tract
Regenerating gene protein may mediate gastric mucosal proliferation induced by hypergastrinemia in rats☆,☆☆