Hydroxylase inhibition attenuates colonic epithelial secretory function and ameliorates experimental diarrhea.
AffiliationMolecular Medicine Laboratories, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland.
MetadataShow full item record
CitationHydroxylase inhibition attenuates colonic epithelial secretory function and ameliorates experimental diarrhea. 2011, 25 (2):535-43 FASEB J.
JournalThe FASEB journal : official publication of the Federation of American Societies for Experimental Biology
AbstractHydroxylases are oxygen-sensing enzymes that regulate cellular responses to hypoxia. Transepithelial Cl(-) secretion, the driving force for fluid secretion, is dependent on O(2) availability for generation of cellular energy. Here, we investigated the role of hydroxylases in regulating epithelial secretion and the potential for targeting these enzymes in treatment of diarrheal disorders. Ion transport was measured as short-circuit current changes across voltage-clamped monolayers of T(84) cells and mouse colon. The antidiarrheal efficacy of dimethyloxallyl glycine (DMOG) was tested in a mouse model of allergic disease. Hydroxylase inhibition with DMOG attenuated Ca(2+)- and cAMP-dependent secretory responses in voltage-clamped T(84) cells to 20.2 ± 2.6 and 38.8 ± 6.7% (n=16; P≤0.001) of those in control cells, respectively. Antisecretory actions of DMOG were time and concentration dependent, being maximal after 18 h of DMOG (1 mM) treatment. DMOG specifically inhibited Na(+)/K(+)-ATPase pump activity without altering its expression or membrane localization. In mice, DMOG inhibited agonist-induced secretory responses ex vivo and prevented allergic diarrhea in vivo. In conclusion, hydroxylases are important regulators of epithelial Cl(-) and fluid secretion and present a promising target for development of new drugs to treat transport disorders.
- Farnesoid X receptor agonists attenuate colonic epithelial secretory function and prevent experimental diarrhoea in vivo.
- Authors: Mroz MS, Keating N, Ward JB, Sarker R, Amu S, Aviello G, Donowitz M, Fallon PG, Keely SJ
- Issue date: 2014 May
- Ursodeoxycholic acid attenuates colonic epithelial secretory function.
- Authors: Kelly OB, Mroz MS, Ward JB, Colliva C, Scharl M, Pellicciari R, Gilmer JF, Fallon PG, Hofmann AF, Roda A, Murray FE, Keely SJ
- Issue date: 2013 May 1
- Cyclic AMP-induced K+ secretion occurs independently of Cl- secretion in rat distal colon.
- Authors: Sandle GI, Rajendran VM
- Issue date: 2012 Aug 1
- Abolition of Ca2+-mediated intestinal anion secretion and increased stool dehydration in mice lacking the intermediate conductance Ca2+-dependent K+ channel Kcnn4.
- Authors: Flores CA, Melvin JE, Figueroa CD, Sepúlveda FV
- Issue date: 2007 Sep 1
- The Epac1 signaling pathway regulates Cl- secretion via modulation of apical KCNN4c channels in diarrhea.
- Authors: Sheikh IA, Koley H, Chakrabarti MK, Hoque KM
- Issue date: 2013 Jul 12