CAMP inhibition of murine intestinal Na +/H + exchange requires CFTR-mediated cell shrinkage of villus epithelium

Abstract

Background & Aims : Unlike the intestine of normal subjects, small-intestinal epithelia of cystic fibrosis patients and cystic fibrosis transmembrane conductance regulator protein-null (CFTR −) mice do not respond to stimulation of intracellular cyclic adenosine monophosphate with inhibition of electroneutral NaCl absorption. Because CFTR-mediated anion secretion has been associated with changes in crypt cell volume, we hypothesized that CFTR-mediated cell volume reduction in villus epithelium is required for intracellular cyclic adenosine monophosphate inhibition of Na +/H + exchanger (primarily Na +/H + exchanger 3) activity in the proximal small intestine. Methods : Transepithelial 22Na flux across the jejuna of CFTR +, CFTR −, the basolateral membrane Na +/K +/2Cl − co-transporter protein NKCC1 +, and NKCC1 − mice were correlated with changes in epithelial cell volume of the midvillus region. Results : Stimulation of intracellular cyclic adenosine monophosphate resulted in cessation of Na +/H + exchanger-mediated Na + absorption (J ms NHE) in CFTR + jejunum but had no effect on J ms NHE across CFTR − jejunum. Cell volume indices indicated an approximately 30% volume reduction of villus epithelial cells in CFTR + jejunum but no changes in CFTR − epithelium after intracellular cyclic adenosine monophosphate stimulation. In contrast, cell shrinkage induced by hypertonic medium inhibited J ms NHE in both CFTR + and CFTR − mice. Bumetanide treatment to inhibit Cl − secretion by blockade of the Na +/K +/2Cl − co-transporter, NKCC1, of stimulated CFTR + jejunum prevented maximal volume reduction of villus epithelium and recovered approximately 40% of J ms NHE. Likewise, J ms NHE and cell volume were unaffected by intracellular cyclic adenosine monophosphate stimulation in NKCC1 − jejuna. Conclusions : These findings show a previously unrecognized role of functional CFTR expressed in villus epithelium: regulation of Na +/H + exchanger 3-mediated Na + absorption by alteration of epithelial cell volume.