title: Hypoxia inhibits colonic ion transport via activation of AMP kinase.
abstract: OBJECTIVE
  Mucosal hypoxia is a common endpoint for many pathological processes including ischemic colitis, colonic obstruction and anastomotic failure. Previous studies suggest that hypoxia modulates colonic mucosal function through inhibition of chloride secretion. However, the molecular mechanisms underlying this observation are poorly understood. AMP-activated protein kinase (AMPK) is a metabolic energy regulator found in a wide variety of cells and has been linked to cystic fibrosis transmembrane conductance regulator (CFTR) mediated chloride secretion in several different tissues. We hypothesized that AMPK mediates many of the acute effects of hypoxia on human and rat colonic electrolyte transport.
  
  
  METHODS
  The fluorescent chloride indicator dye N-(ethoxycarbonylmethyl)-6-methoxyquinolinium bromide was used to measure changes in intracellular chloride concentrations in isolated single rat colonic crypts. Ussing chamber experiments in human colonic mucosa were conducted to evaluate net epithelial ion transport.
  
  
  RESULTS
  This study demonstrates that acute hypoxia inhibits electrogenic chloride secretion via AMPK mediated inhibition of CFTR. Pre-treatment of tissues with the AMPK inhibitor 6-[4-(2-piperidin-1-yl-ethoxy)-phenyl)]-3-pyridin-4-yl-pyyrazolo [1,5-a] pyrimidine (compound C) in part reversed the effects of acute hypoxia on chloride secretion.
  
  
  CONCLUSIONS
  We therefore suggest that AMPK is a key component of the adaptive cellular response to mucosal hypoxia in the colon. Furthermore, AMPK may represent a potential therapeutic target in diseased states or in prevention of ischemic intestinal injury.
authors.affiliation: University College Dublin and St Vincent's University Hospital, Elm Park, Dublin, Ireland.
authors.forename: Danielle
authors.initials: D
authors.lastname: Collins
authors.forename: Sascha
authors.initials: S
authors.lastname: Kopic
authors.forename: Julia
authors.initials: J
authors.lastname: Bachlechner
authors.forename: Markus
authors.initials: M
authors.lastname: Ritter
authors.forename: Desmond C
authors.initials: DC
authors.lastname: Winter
authors.forename: John P
authors.initials: JP
authors.lastname: Geibel
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000502:physiology*; D000818:Animals; D015687:Cell Hypoxia / Q000502:physiology*; D018118:Chloride Channels / Q000502:physiology*; D002712:Chlorides / Q000378:metabolism*; D003106:Colon / Q000098:blood supply*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000037:antagonists & inhibitors*; D006801:Humans; D007413:Intestinal Mucosa / Q000098:blood supply*; D007511:Ischemia / Q000503:physiopathology*; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D008856:Microscopy, Fluorescence; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D018118:Chloride Channels; D002712:Chlorides; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D055372:AMP-Activated Protein Kinases