Loss of Claudin-15, but Not Claudin-2, Causes Na+ Deficiency and Glucose Malabsorption in Mouse Small Intestine
Loss of Claudin-15, but Not Claudin-2, Causes Na+ Deficiency and Glucose Malabsorption in Mouse Small Intestine
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DOI：
10.1053/j.gastro.2010.08.006
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发表时间：
2011-03-01
期刊：
影响因子：
29.4
通讯作者：
Tsukita, Sachiko
中科院分区：
文献类型：
--
作者：
Tamura, Atsushi;Hayashi, Hisayoshi;Tsukita, Sachiko
背景与目的：在小肠中，Na+的细胞旁转运被认为对于腔Na+稳态和Na+驱动的转运蛋白对营养物的跨细胞吸收至关重要。Na+通过紧密连接从粘膜下层和血清供应到肠腔，紧密连接在上皮片的细胞之间形成细胞旁屏障。然而，这种Na+的细胞旁转运的分子基础还不清楚。在这里，我们研究了这一机制，进行claudin-2和claudin-15，两个紧密连接的膜蛋白，特异性和年龄依赖性表达的绒毛和/或隐窝的小肠上皮细胞的功能丧失的研究。方法：对claudin-2或claudin-15基因敲除小鼠进行组织学、细胞生物学、电生理学和生理学分析。研究结果：对敲除小鼠的检查显示，在婴儿和成人中，密蛋白-2和15在细胞外单价阳离子（特别是Na+）的跨上皮细胞旁通道样选择性渗透中起关键作用。特别是在Cldn 15（-/-）成人中，在体内直接测量的小肠腔Na+浓度异常低，葡萄糖吸收受损，通过口服葡萄糖耐量试验和未吸收葡萄糖的估计进行评估。结论：我们提出，“Na+-渗漏”claudin-15是不可缺少的在体内的细胞旁Na+渗透性，管腔Na+-稳态，并在小肠中有效的葡萄糖吸收，但claudin-2是不可缺少的，只有第一个这些功能。Claudin-15基因敲除导致成年小鼠小肠Na+缺乏和葡萄糖吸收不良。
BACKGROUND & AIMS: In the small intestine, the paracellular transport of Na+ is thought to be critical for luminal Na+-homeostasis and the transcellular absorption of nutrients by Na+-driven transporters. Na+ is supplied to the intestinal lumen from the submucosa and serum through tight junctions, which form a paracellular barrier between the cells of epithelial sheets. However, the molecular basis for this paracellular transport of Na+ is not well understood. Here, we examined this mechanism by performing loss-of-function studies of claudin-2 and claudin-15, two tight-junctional membrane proteins that are specifically and age-dependently expressed in the villi and/or crypts of small intestinal epithelia. METHODS: Knockout mice for claudin-2 or claudin-15 were subjected to histologic, cell biologic, electrophysiologic, and physiologic analyses. RESULTS: Examination of the knockout mice revealed that both claudin-2 and claudin-15 play crucial roles in the transepithelial paracellular channel-like permselectivity for extracellular monovalent cations, particularly Na+, in infants and adults. Especially in Cldn15(-/-) adults, the luminal Na+ concentration in the small intestine measured directly in vivo was abnormally low, and glucose absorption was impaired, as assessed by the oral glucose tolerance test and estimation of unabsorbed glucose. CONCLUSIONS: We propose that the "Na+-leaky" claudin-15 is indispensable in vivo for the paracellular Na+ permeability, luminal Na+-homeostasis, and efficient glucose absorption in the small intestine, but claudin-2 is indispensable for only the first of these functions. Claudin-15 knockout leads to Na+ deficiency and glucose malabsorption in the mouse adult small intestine.