title: Loss of claudin-15, but not claudin-2, causes Na+ deficiency and glucose malabsorption in mouse small intestine.
abstract: 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.
authors: Laboratory of Biological Science, Graduate School of Frontier Biosciences and Graduate School of Medicine, Osaka University, Yamadaoka, Suita, Osaka, Japan.
authors: Atsushi
authors: A
authors: Tamura
authors: Hisayoshi
authors: H
authors: Hayashi
authors: Mitsunobu
authors: M
authors: Imasato
authors: Yuji
authors: Y
authors: Yamazaki
authors: Asuka
authors: A
authors: Hagiwara
authors: Masami
authors: M
authors: Wada
authors: Tetsuo
authors: T
authors: Noda
authors: Mitsuhiro
authors: M
authors: Watanabe
authors: Yuichi
authors: Y
authors: Suzuki
authors: Sachiko
authors: S
authors: Tsukita
mesh_terms: 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
chemical_list: D057167:Claudins; C113371:Cldn2 protein, mouse; D008565:Membrane Proteins; C459596:claudin 15; D012964:Sodium; D005947:Glucose; D011188:Potassium