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MUCOSAL BIOLOGY

Electroneutral sodium absorption and electrogenic anion secretion across murine small intestine are regulated in parallel

¹Dalton Cardiovascular Research Center and the Department of Biomedical Sciences, University of Missouri-Columbia, Columbia, Missouri 65211; ²Department of Molecular Genetics, Biochemistry and Microbiology and ³Environmental Health, University of Cincinnati, College of Medicine, Cincinnati, Ohio 45267; and ⁴Department of Biochemistry, Erasmus University Medical Center, 3000 DR Rotterdam, The Netherlands

Submitted 19 April 2004 ; accepted in final form 22 July 2004

Electrolyte transport processes of small intestinal epithelia maintain a balance between hydration of the luminal contents and systemic fluid homeostasis. Under basal conditions, electroneutral Na⁺ absorption mediated by Na⁺/H⁺ exchanger 3 (NHE3) predominates; under stimulated conditions, increased anion secretion mediated by CFTR occurs concurrently with inhibition of Na⁺ absorption. Homeostatic adjustments to diseases that chronically affect the activity of one transporter (e.g., cystic fibrosis) may include adaptations in the opposing transport process to prevent enterosystemic fluid imbalance. To test this hypothesis, we measured electrogenic anion secretion (indexed by the short-circuit current) across NHE3-null [NHE3(–)] murine small intestine and electroneutral Na⁺ absorption (by radioisotopic flux analysis) across small intestine of mice with gene-targeted disruptions of the anion secretory pathway, i.e., CFTR-null [CFTR(–)] or Na⁺-K⁺-2Cl^– cotransporter-null [NKCC1(–)]. Protein expression of NHE3 and CFTR in the intestinal epithelia was measured by immunoblotting. In NHE3(–), compared with wild-type small intestine, maximal and bumetanide-sensitive anion secretion following cAMP stimulation was significantly reduced, and there was a corresponding decrease in CFTR protein expression. In CFTR(–) and NKCC1(–) intestine, Na⁺ absorption was significantly reduced compared with wild-type. NHE3 protein expression was decreased in the CFTR(–) intestine but was unchanged in the NKCC1(–) intestine, indicating that factors independent of expression also downregulate NHE3 activity. Together, these data support the concept that absorptive and secretory processes determining NaCl and water movement across the intestinal epithelium are regulated in parallel to maintain balance between the systemic fluid volume and hydration of the luminal contents.

Na⁺/H⁺ exchanger; cystic fibrosis transmembrane conductance regulator; Na⁺-K⁺-2Cl^– cotransporter; cystic fibrosis; chloride

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