Loss of claudin-15, but not claudin-2, causes Na+ deficiency and glucose malabsorption in mouse small intestine

Atsushi Tamura, Hisayoshi Hayashi, Mitsunobu Imasato, Yuji Yamazaki, Asuka Hagiwara, Masami Wada, Tetsuo Noda, Mitsuhiro Watanabe, Yuichi Suzuki, Sachiko Tsukita

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)913-923
Number of pages11
JournalGastroenterology
Volume140
Issue number3
DOIs
Publication statusPublished - 2011 Mar

Fingerprint

Claudin-2
Small Intestine
Glucose
Knockout Mice
Homeostasis
Monovalent Cations
Tight Junctions
Intestinal Mucosa
Glucose Tolerance Test
Permeability
Membrane Proteins
Epithelial Cells
claudin 15
Food
Serum

Keywords

  • Tight Junction; Na-Homeostasis; Glucose Absorption

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Tamura, A., Hayashi, H., Imasato, M., Yamazaki, Y., Hagiwara, A., Wada, M., ... Tsukita, S. (2011). Loss of claudin-15, but not claudin-2, causes Na+ deficiency and glucose malabsorption in mouse small intestine. Gastroenterology, 140(3), 913-923. https://doi.org/10.1053/j.gastro.2010.08.006

Loss of claudin-15, but not claudin-2, causes Na+ deficiency and glucose malabsorption in mouse small intestine. / Tamura, Atsushi; Hayashi, Hisayoshi; Imasato, Mitsunobu; Yamazaki, Yuji; Hagiwara, Asuka; Wada, Masami; Noda, Tetsuo; Watanabe, Mitsuhiro; Suzuki, Yuichi; Tsukita, Sachiko.

In: Gastroenterology, Vol. 140, No. 3, 03.2011, p. 913-923.

Research output: Contribution to journalArticle

Tamura, A, Hayashi, H, Imasato, M, Yamazaki, Y, Hagiwara, A, Wada, M, Noda, T, Watanabe, M, Suzuki, Y & Tsukita, S 2011, 'Loss of claudin-15, but not claudin-2, causes Na+ deficiency and glucose malabsorption in mouse small intestine', Gastroenterology, vol. 140, no. 3, pp. 913-923. https://doi.org/10.1053/j.gastro.2010.08.006
Tamura, Atsushi ; Hayashi, Hisayoshi ; Imasato, Mitsunobu ; Yamazaki, Yuji ; Hagiwara, Asuka ; Wada, Masami ; Noda, Tetsuo ; Watanabe, Mitsuhiro ; Suzuki, Yuichi ; Tsukita, Sachiko. / Loss of claudin-15, but not claudin-2, causes Na+ deficiency and glucose malabsorption in mouse small intestine. In: Gastroenterology. 2011 ; Vol. 140, No. 3. pp. 913-923.
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T1 - Loss of claudin-15, but not claudin-2, causes Na+ deficiency and glucose malabsorption in mouse small intestine

AU - Tamura, Atsushi

AU - Hayashi, Hisayoshi

AU - Imasato, Mitsunobu

AU - Yamazaki, Yuji

AU - Hagiwara, Asuka

AU - Wada, Masami

AU - Noda, Tetsuo

AU - Watanabe, Mitsuhiro

AU - Suzuki, Yuichi

AU - Tsukita, Sachiko

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N2 - 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.

AB - 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.

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