Annals of Surgery 2011-12-01

Hypoxia inhibits colonic ion transport via activation of AMP kinase.

Danielle Collins, Sascha Kopic, Julia Bachlechner, Markus Ritter, Desmond C Winter, John P Geibel

Index: Ann. Surg. 254 , 957-963, (2011)

Full Text: HTML

Abstract

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.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.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.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.


Related Compounds

Related Articles:

Synthesis and characterization of improved chloride-sensitive fluorescent indicators for biological applications.

1989-05-01

[Anal. Biochem. 178 , 355, (1989)]

The membrane-bound bile acid receptor TGR5 is localized in the epithelium of human gallbladders.

2009-09-01

[Hepatology 50 , 861-870, (2009)]

Synthetic ion transporters can induce apoptosis by facilitating chloride anion transport into cells.

2014-10-01

[Nature Chemistry 6(10) , 885-92, (2014)]

Na+,K+,2Cl- cotransport and intracellular chloride regulation in rat primary sensory neurons: thermodynamic and kinetic aspects.

2008-07-01

[J. Neurophysiol. 100 , 169-84, (2008)]

GABA-mediated repulsive coupling between circadian clock neurons in the SCN encodes seasonal time.

2015-07-21

[Proc. Natl. Acad. Sci. U. S. A. 112 , E3920-9, (2015)]

More Articles...