Hypoxia inhibits colonic ion transport via activation of AMP kinase.
Collins, Danielle Kopic, Sascha Bachlechner, Julia Ritter, Markus Winter, Desmond C Geibel, John P
Collins, Danielle
Kopic, Sascha
Bachlechner, Julia
Ritter, Markus
Winter, Desmond C
Geibel, John P
Advisors
Editors
Other Contributors
Date
2012-02-01T10:28:08Z
Date Submitted
Keywords
Other Subjects
Subject Mesh
AMP-Activated Protein Kinases/*physiology
Animals
Cell Hypoxia/*physiology
Chloride Channels/*physiology
Chlorides/*metabolism
Colon/*blood supply
Cystic Fibrosis Transmembrane Conductance Regulator/*antagonists & inhibitors
Humans
Intestinal Mucosa/*blood supply
Ischemia/*physiopathology
Male
Membrane Potentials/physiology
Microscopy, Fluorescence
Rats
Rats, Sprague-Dawley
Animals
Cell Hypoxia/*physiology
Chloride Channels/*physiology
Chlorides/*metabolism
Colon/*blood supply
Cystic Fibrosis Transmembrane Conductance Regulator/*antagonists & inhibitors
Humans
Intestinal Mucosa/*blood supply
Ischemia/*physiopathology
Male
Membrane Potentials/physiology
Microscopy, Fluorescence
Rats
Rats, Sprague-Dawley
Planned Date
Start Date
Collaborators
Principal Investigators
Alternative Titles
Publisher
Abstract
BACKGROUND AND AIMS: 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. CONCLUSION: 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.
Language
eng
Citation
ISSN
1528-1140 (Electronic)
0003-4932 (Linking)
0003-4932 (Linking)
eISSN
ISBN
DOI
10.1097/SLA.0b013e31821d477f
PMID
21562404