Tight junction proteins claudin-2 and -12 are critical for vitamin D-dependent Ca2+ absorption between enterocytes
Tight junction proteins claudin-2 and -12 are critical for vitamin D-dependent Ca2+ absorption between enterocytes
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DOI：
10.1091/mbc.e07-09-0973
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发表时间：
2008-05-01
影响因子：
3.3
通讯作者：
Chiba, Hideki
中科院分区：
文献类型：
--
作者：
Fujita, Hiroki;Sugimoto, Kotaro;Chiba, Hideki
Ca（2+）通过跨细胞和细胞旁途径跨肠上皮单层吸收，并且已知维生素D（3）的活性形式1 α，25-二羟基维生素D（3）[1 α，25（OH）（2）D（3）]促进肠Ca（2+）吸收。然而，驱动细胞旁Ca（2+）吸收及其维生素D依赖性的分子仍然不清楚。由于紧密连接蛋白claudin被认为在相邻细胞之间形成选择性离子的细胞旁通道，我们假设特定的肠claudin可能促进细胞旁Ca（2+）转运，并且这些claudin的表达可以被1 α，25（OH）（2）D诱导（3）。在此，我们通过使用RNA干扰和过表达策略表明，claudin-2和claudin-12有助于肠上皮细胞中的Ca（2+）吸收。我们还提供了证据表明，1 α，25（OH）（2）D（3）通过维生素D受体在体外和体内肠上皮细胞中上调了claudins-2和-12的表达。这些发现强烈表明，基于密蛋白-2和/或密蛋白-12的紧密连接在肠上皮细胞中形成细胞旁Ca（2+）通道，并且它们突出了维生素D依赖性钙稳态背后的新机制。
Ca(2+) is absorbed across intestinal epithelial monolayers via transcellular and paracellular pathways, and an active form of vitamin D(3), 1 alpha,25-dihydroxyvitamin D(3) [1 alpha,25(OH)(2)D(3)], is known to promote intestinal Ca(2+) absorption. However, the molecules driving the paracellular Ca(2+) absorption and its vitamin D dependency remain obscure. Because the tight junction proteins claudins are suggested to form paracellular channels for selective ions between neighboring cells, we hypothesized that specific intestinal claudins might facilitate paracellular Ca(2+) transport and that expression of these claudins could be induced by 1 alpha, 25(OH)(2)D(3). Herein, we show, by using RNA interference and overexpression strategies, that claudin-2 and claudin-12 contribute to Ca(2+) absorption in intestinal epithelial cells. We also provide evidence showing that expression of claudins-2 and -12 is up-regulated in enterocytes in vitro and in vivo by 1 alpha,25(OH)(2)D(3) through the vitamin D receptor. These findings strongly suggest that claudin-2- and/or claudin-12-based tight junctions form paracellular Ca(2+) channels in intestinal epithelia, and they highlight a novel mechanism behind vitamin D-dependent calcium homeostasis.