Loss of claudin-15, but not claudin-2, causes Na+ deficiency and glucose malabsorption in mouse small intestine.
OBJECTIVE
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.
Tamura
Atsushi
A
Laboratory of Biological Science, Graduate School of Frontier Biosciences and Graduate School of Medicine, Osaka University, Yamadaoka, Suita, Osaka, Japan.
Hayashi
Hisayoshi
H
Imasato
Mitsunobu
M
Yamazaki
Yuji
Y
Hagiwara
Asuka
A
Wada
Masami
M
Noda
Tetsuo
T
Watanabe
Mitsuhiro
M
Suzuki
Yuichi
Y
Tsukita
Sachiko
S
D000367:Age Factors; D000818:Animals; D057167:Claudins; D004553:Electric Conductivity; D004847:Epithelial Cells / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D006706:Homeostasis; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology; D007421:Intestine, Small / Q000378:metabolism* / Q000473:pathology; D008286:Malabsorption Syndromes / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D010539:Permeability; D011188:Potassium / Q000378:metabolism; D012964:Sodium / Q000172:deficiency*; D019108:Tight Junctions / Q000378:metabolism; D013997:Time Factors
D057167:Claudins; C113371:Cldn2 protein, mouse; D008565:Membrane Proteins; C459596:claudin 15; D012964:Sodium; D005947:Glucose; D011188:Potassium