Laboratory of Biological Science, Graduate School of Frontier Biosciences and Graduate School of Medicine, Osaka University, Yamadaoka, Suita, Osaka, Japan.
Gastroenterology. 2011 Mar;140(3):913-23. doi: 10.1053/j.gastro.2010.08.006. Epub 2010 Aug 18.
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.
Knockout mice for claudin-2 or claudin-15 were subjected to histologic, cell biologic, electrophysiologic, and physiologic analyses.
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.
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.
在小肠中，细胞旁转运的 Na(+) 被认为对腔内 Na(+) 稳态和 Na(+)-驱动转运蛋白介导的营养物质的跨细胞吸收至关重要。Na(+) 通过紧密连接从黏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(+) 细胞旁转运的分子基础尚未得到很好的理解。在这里，我们通过对 Claudin-2 和 Claudin-15 进行功能丧失研究来研究这种机制，Claudin-2 和 Claudin-15 是两种紧密连接的膜蛋白，它们在小肠上皮的绒毛和/或隐窝中特异性和年龄依赖性表达。
对 Claudin-2 或 Claudin-15 的敲除小鼠进行组织学、细胞生物学、电生理学和生理学分析。
对敲除小鼠的检查表明，Claudin-2 和 Claudin-15 都在婴儿和成人的跨上皮细胞旁通道样对细胞外单价阳离子（尤其是 Na(+)）的选择性渗透性中发挥关键作用。特别是在 Cldn15(-/-) 成年小鼠中，体内直接测量的小肠腔内 Na(+) 浓度异常低，口服葡萄糖耐量试验和未吸收葡萄糖的估计表明葡萄糖吸收受损。
我们提出，“Na(+)渗漏” Claudin-15 在体内对于小肠的细胞旁 Na(+) 通透性、腔内 Na(+) 稳态和有效的葡萄糖吸收是不可或缺的，但 Claudin-2 对于这些功能中的第一个是不可或缺的。Claudin-15 敲除导致成年小鼠小肠 Na(+) 缺乏和葡萄糖吸收不良。
