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Ghrelin dynamics in mice with genetically knockout of basolateral membranous receptor of the parietal cell

壁细胞基底外侧膜受体基因敲除小鼠的生长素释放肽动力学

基本信息

批准号：
17590675
负责人：
SUZUKI Hidekazu
金额：
$ 2.24万
依托单位：
KEIO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590675/
关键词：
ghrelin parietal cell histamine type 2 receptor muscarine type 3 receptor acid food intake body weight A-like cell H. pylori

项目摘要

Ghrelin, an appetite-promoting peptide secreted from the stomach, is reported to enhance the pre-prandial acid output possibly through the stimulation of cephalic phase, and is also supposed to be affected by parasympathetic, presumably muscarinic signaling. Among five subtypes (M_1-M_5) of muscarinic acetylcholine receptors, M_3 is known to be expressed on the surface of parietal cells, which are located in the vicinity of the ghrelin-producing A-like cells. The present study was designed to clarify the dynamics of the ghrelin in mice with genetically knockout (KO) of H_2 receptor (H_2R) or M_3 receptor (M_3R) on the basolateral membrane of the parietal cell. Methods. Fifteen-and 54-week-old H_2R-KO mice and 25-week-old M_3R KO mice were compared with their littermates. After evaluating the levels of food intakes and body weight increment, mice were sacrificed to examine the plasma active and total ghrelin levels, gastric active and total ghrelin levels by RIA, and the gastric preprog … More hrelin mRNA expression by quantitative RT-PCR. Furthermore, some stomach specimens were evaluated by immunohistochemistry and transmission electron microscopy for ghrelin. Results. The levels of food intakes and body weight gain of the H_2R-K0 mice were higher than those of wild type mice. The gastric pH in the 54-week-old H_2R-K0 mice was lower than those of 15-week-old mice. Gastric preproghrelin mRNA expression, plasma ghrelin level and percentage of ghrelin-immunoreactive cells in the gastric mucosa of the H_2R-K0 mice were significantly increased as compared with those of wild types. Ghrelin-positive immunogold density in the electron micrograph was significantly reduced in A-like cells of H_2R-KO mouse stomach. On the other hand, although body weight of M_3R KO mice was significantly decreased, which possibly reflected its malnutrition, their plasma ghrelin levels and numbers of ghrelin-immunoreactive cells in the gastric mucosa were not significantly elevated as compared with those of wild type mice. On the other hand, preproghrelin mRNA expression and gastric ghrelin contents were significantly increased in M_3R-KO mice as compared with those of wild types. Conclusion. While ghrelin production and secretion from A-like cells in the gastric fundus are upregulated in mice with genetically H_2R-KO as a compensatory mechanism for H_2R blockade, only the ghrelin production, not but its secretion from A-like cells, are upregulated in mice with M_3R-KO. These results suggest that H_2R blockade affects the ghrelin dynamics through the inhibition of acid secretion and that M_3R plays an important and direct role for ghrelin secretion from A-like cells of the stomach. Less

Ghrelin是一种由胃分泌的促进食欲的肽，据报道可能通过刺激头期来增强餐前酸输出，并且还被认为受到副交感神经（推测为毒蕈碱信号）的影响。在M_1-M_5五种亚型中，M_3表达于壁细胞表面，位于产生ghrelin的A样细胞附近。本研究旨在阐明壁细胞基底外侧膜H_2受体（H_2R）和M_3受体（M_3R）基因敲除（KO）小鼠胃饥饿素（ghrelin）的动态变化。方法.将15、54周龄的H_2 R-KO小鼠和25周龄的M_3R-KO小鼠与同窝小鼠进行比较。在评估摄食量和体重增长水平后，处死小鼠，用放射免疫法检测血浆活性和总ghrelin水平，胃活性和总ghrelin水平，以及胃前体素水平。 ...更多信息 hrelin mRNA表达。此外，通过免疫组织化学和透射电子显微镜对一些胃标本进行了ghrelin的评价。结果H2 R-K 0小鼠的摄食量和体重增长水平均高于野生型小鼠。54周龄H_2 R-K_0小鼠胃内pH值低于15周龄小鼠。与野生型小鼠相比，H2 R-K 0小鼠胃组织中ghrelin前体mRNA表达、血浆ghrelin水平和胃粘膜ghrelin免疫反应阳性细胞百分比均显著升高。电镜下，H_2 R-KO小鼠胃A样细胞Ghrelin阳性免疫金密度明显降低。另一方面，M_3R KO小鼠体重明显下降，可能反映了其营养不良，但血浆ghrelin水平和胃粘膜ghrelin免疫反应阳性细胞数与野生型小鼠相比无明显升高。与野生型小鼠相比，M3 R-KO小鼠胃组织中前促生长素原mRNA表达和胃促生长素含量显著增加。结论H2 R-KO小鼠胃底A样细胞Ghrelin的产生和分泌上调，这是对H2 R阻断的一种代偿机制，而M_3R-KO小鼠胃底A样细胞Ghrelin的分泌上调，而A样细胞Ghrelin的产生和分泌上调。这些结果提示H_2R阻断可通过抑制胃酸分泌而影响Ghrelin的动力学，而M_3R对胃A样细胞Ghrelin的分泌起重要而直接的作用。少