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Impaired enterocyte proliferation in aquaporin-3 deficiency in mouse models of colitis
  1. Jay R Thiagarajah,
  2. Dan Zhao,
  3. A S Verkman
  1. Departments of Medicine and Physiology, Cardiovascular Research Institute, University of California, San Francisco, CA 94143-0521, USA
  1. Alan S Verkman, MD, PhD, 1246 Health Sciences East Tower, Cardiovascular Research Institute, University of California, San Francisco, CA 94143-0521, USA; verkman{at}itsa.ucsf.edu

Abstract

Background/Aims: Recent evidence has implicated the involvement of aquaporins (AQPs) in cellular functions that are unrelated to transepithelial water transport. Although AQPs are expressed in the gastrointestinal tract, their importance has so far been unclear. AQP3 is a water/glycerol transporter expressed at the basolateral membrane of colonic epithelial cells. The aim of this study was to investigate the involvement of AQP3 in enterocyte proliferation using mouse models of inflammatory bowel disease.

Methods: Expression and function of AQP3 in mouse colonic epithelium were established. Colitis was induced in wild-type and AQP3 null mice by oral dextran sulphate administration or intracolonic acetic acid administration. Outcome measures included clinical disease severity, survival, pathology and cellular responses. Some mice were administered glycerol to test whether disease progression could be altered.

Results: AQP3 null mice given dextran sulphate developed severe colitis after 3 days, with colonic haemorrhage, marked epithelial cell loss and death. Wild-type mice, which had comparable initial colonic damage as assessed by cell apoptosis, developed remarkably less severe colitis, surviving to >8 days. Cell proliferation was greatly reduced in AQP3 null mice. Oral glycerol administration significantly improved survival and reduced the severity of colitis in AQP3 null mice. Survival was also reduced in AQP3 null mice in the acetic acid model.

Conclusions: The results implicate a novel role for AQP3 in enterocyte proliferation that is probably related to its glycerol-transporting function. AQP3 is thus a potential target for therapy of intestinal diseases associated with enterocyte destruction.

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Footnotes

  • Competing interests: None.

  • Abbreviations:
    AQP
    aquaporin
    BrdU
    bromodeoxyuridine
    DAI
    disease activity index
    IBD
    inflammatory bowel disease
    PPAR
    peroxisome proliferator-activated receptor
    TLR
    Toll-like receptor

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