Mice with a targeted disruption of the AE2 Cl-/HCO3- exchanger are achlorhydric
Mice with a targeted disruption of the AE2 Cl-/HCO3- exchanger are achlorhydric
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DOI：
10.1074/jbc.m403779200
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发表时间：
2004-07-16
影响因子：
4.8
通讯作者：
Shull, GE
中科院分区：
文献类型：
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作者：
Gawenis, LR;Ledoussal, C;Shull, GE
AE2Cl-/HCO3-交换器在多种细胞类型中表达，包括肾脏、呼吸道和消化道的上皮细胞。在胃上皮细胞中，AE2在壁细胞中尤其丰富，这可能是HCO3-外流和Cl-内流穿过胃酸分泌所需的基侧膜的主要机制。为了研究AE2对壁细胞功能至关重要的假设，并评估其在其他组织中的重要性，通过靶向阻断AE2(SLC4a2)基因制备了纯合子零突变(AE2(-/-))小鼠。AE2(-/-)小鼠消瘦、无牙(无牙)，并表现出严重的生长迟缓，大多数在断奶时死亡。AE2(-/-)小鼠表现出酸痛，组织学研究显示胃上皮细胞异常，包括胃腺腔中度扩张和壁细胞数量减少。然而，几乎没有证据表明壁细胞的活力受到了损害。AE2(-/-)胃粘膜超微结构显示壁细胞结构异常，分泌小管发育严重受损，管泡稀少，顶端微绒毛正常。这些结果表明，AE2对胃酸分泌和小鼠壁细胞分泌小管和管泡膜的正常发育是必需的。
The AE2 Cl-/HCO3- exchanger is expressed in numerous cell types, including epithelial cells of the kidney, respiratory tract, and alimentary tract. In gastric epithelia, AE2 is particularly abundant in parietal cells, where it may be the predominant mechanism for HCO3- efflux and Cl- influx across the basolateral membrane that is needed for acid secretion. To investigate the hypothesis that AE2 is critical for parietal cell function and to assess its importance in other tissues, homozygous null mutant (AE2(-/-)) mice were prepared by targeted disruption of the AE2 (Slc4a2) gene. AE2(-/-) mice were emaciated, edentulous (toothless), and exhibited severe growth retardation, and most of them died around the time of weaning. AE2(-/-) mice exhibited achlorhydria, and histological studies revealed abnormalities of the gastric epithelium, including moderate dilation of the gastric gland lumens and a reduction in the number of parietal cells. There was little evidence, however, that parietal cell viability was impaired. Ultrastructural analysis of AE2(-/-) gastric mucosa revealed abnormal parietal cell structure, with severely impaired development of secretory canaliculi and few tubulovesicles but normal apical microvilli. These results demonstrate that AE2 is essential for gastric acid secretion and for normal development of secretory canalicular and tubulovesicular membranes in mouse parietal cells.