Tight junction proteins claudin-2 and -12 are critical for vitamin D-dependent Ca2+ absorption between enterocytes

• Published in: Molecular biology of the cell Vol. 19; no. 5; pp. 1912 - 1921
• Main Authors: Fujita, Hiroki, Sugimoto, Kotaro, Inatomi, Shuichiro, Maeda, Toshihiro, Osanai, Makoto, Uchiyama, Yasushi, Yamamoto, Yoko, Wada, Takuro, Kojima, Takashi, Yokozaki, Hiroshi, Yamashita, Toshihiko, Kato, Shigeaki, Sawada, Norimasa, Chiba, Hideki
• Format: Journal Article
• Language: English
• Published: United States The American Society for Cell Biology 01-05-2008
• Subjects: Animals; Biological Transport - drug effects; Caco-2 Cells; Calcium - metabolism; Cell Membrane Permeability - drug effects; Claudins; Down-Regulation - drug effects; Enterocytes - drug effects; Enterocytes - metabolism; Humans; Intestinal Absorption - drug effects; Intestines - cytology; Intestines - metabolism; Membrane Proteins - metabolism; Mice; Mice, Knockout; Receptors, Calcitriol - deficiency; Receptors, Calcitriol - metabolism; Sodium - metabolism; Tight Junctions - drug effects; Tight Junctions - metabolism; Vitamin D - analogs & derivatives; Vitamin D - pharmacology
• ISSN: 1059-1524; 1939-4586
• DOI: 10.1091/mbc.e07-09-0973

Ca(2+) is absorbed across intestinal epithelial monolayers via transcellular and paracellular pathways, and an active form of vitamin D(3), 1alpha,25-dihydroxyvitamin D(3) [1alpha,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 1alpha,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 1alpha,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.