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

LR Gawenis, CL Franklin, JE Simpson, BA Palmer… - Gastroenterology, 2003 - Elsevier
LR Gawenis, CL Franklin, JE Simpson, BA Palmer, NM Walker, TM Wiggins, LL Clarke
Gastroenterology, 2003Elsevier
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 …
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 (JmsNHE) in CFTR+ jejunum but had no effect on JmsNHE 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 JmsNHE 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 JmsNHE. Likewise, JmsNHE 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.
Elsevier