HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Supplemental Figures and Tables All Versions of this Article: 296/4/G886    most recent 90520.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Bradford, E. M. Articles by Shull, G. E. Search for Related Content PubMed PubMed Citation Articles by Bradford, E. M. Articles by Shull, G. E.

MUCOSAL BIOLOGY

Reduced NHE3-mediated Na⁺ absorption increases survival and decreases the incidence of intestinal obstructions in cystic fibrosis mice

¹Department of Molecular Genetics, Biochemistry and Microbiology and ²Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, Ohio; ³Department of Physiology, University of Utah, Salt Lake City, Utah; and ⁴Dalton Cardiovascular Research Center and the Department of Biomedical Sciences, University of Missouri, Columbia, Missouri

Submitted 28 August 2008 ; accepted in final form 14 January 2009

In cystic fibrosis, impaired secretion resulting from loss of activity of the cystic fibrosis transmembrane conductance regulator (CFTR) causes dehydration of intestinal contents and life-threatening obstructions. Conversely, impaired absorption resulting from loss of the NHE3 Na⁺/H⁺ exchanger causes increased fluidity of the intestinal contents and diarrhea. To test the hypothesis that reduced NHE3-mediated absorption could increase survival and prevent some of the intestinal pathologies of cystic fibrosis, Cftr/Nhe3 double heterozygous mice were mated and their offspring analyzed. Cftr-null mice lacking one or both copies of the NHE3 gene exhibited increased fluidity of their intestinal contents, which prevented the formation of obstructions and increased survival. Goblet cell hyperplasia was eliminated, but not the accumulation of Paneth cell granules or increased cell proliferation in the crypts. Microarray analysis of small intestine RNA from Cftr-null, NHE3-null, and double-null mice all revealed downregulation of genes involved in xenobiotic metabolism, including a cohort of genes involved in glutathione metabolism. Expression of energy metabolism genes was altered, but there were no changes in genes involved in inflammation. Total intracellular glutathione was increased in the jejunum of all of the mutants and the ratio of reduced to oxidized glutathione was reduced in Cftr-null mutants, indicating that CFTR deficiency affects intestinal glutathione metabolism. The data establish a major role for NHE3 in regulating the fluidity of the intestinal contents and show that reduced NHE3-mediated absorption reverses some of the intestinal pathologies of cystic fibrosis, thus suggesting that it may serve as a potential therapeutic target.

Slc9a3; distal intestinal obstructive syndrome; meconium ileus; cytochrome P-450; glutathione transferase