Tight junction proteins claudin-2 and -12 are critical for vitamin D-dependent Ca2+ absorption between enterocytes.
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.
Fujita
Hiroki
H
Departments of Pathology and Orthopedic Surgery, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan.
Sugimoto
Kotaro
K
Inatomi
Shuichiro
S
Maeda
Toshihiro
T
Osanai
Makoto
M
Uchiyama
Yasushi
Y
Yamamoto
Yoko
Y
Wada
Takuro
T
Kojima
Takashi
T
Yokozaki
Hiroshi
H
Yamashita
Toshihiko
T
Kato
Shigeaki
S
Sawada
Norimasa
N
Chiba
Hideki
H
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D018938:Caco-2 Cells; D002118:Calcium / Q000378:metabolism*; D002463:Cell Membrane Permeability / Q000187:drug effects; D057167:Claudins; D015536:Down-Regulation / Q000187:drug effects; D020895:Enterocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects*; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000166:cytology; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018167:Receptors, Calcitriol / Q000172:deficiency / Q000378:metabolism; D012964:Sodium / Q000378:metabolism; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism*; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000494:pharmacology
C522352:CLDN12 protein, human; C491875:CLDN2 protein, human; D057167:Claudins; C113371:Cldn2 protein, mouse; D008565:Membrane Proteins; D018167:Receptors, Calcitriol; C488754:claudin 12 protein, mouse; C118756:dihydroxy-vitamin D3; D014807:Vitamin D; D012964:Sodium; D002118:Calcium