Butyrate increases apical membrane CFTR but reduces chloride secretion in MDCK cells

Sodium butyrate and its derivatives are useful therapeutic agents for the t reatment of genetic diseases including urea cycle disorders, sickle cell di sease, thalassemias, and possibly cystic fibrosis (CF). Butyrate partially restores cAMP-activated Cl- secretion in CF epithelial cells by stimulating Delta F508 cystic fibrosis transmembrane conductance regulator (Delta F508 -CFTR) gene expression and increasing the amount of Delta F508-CFTR in the plasma membrane. Because the effect of butyrate on Cl- secretion by renal e pithelial cells has not been reported, we examined the effects of chronic b utyrate treatment (15-18 h) on the function, expression, and localization o f CFTR fused to the green fluorescent protein (GFP-CFTR) in stably transfec ted MDCK cells. We report that sodium butyrate reduced Cl- secretion across MDCK cells, yet increased apical membrane GFP-CFTR expression 25-fold and increased apical membrane Cl- currents 30-fold. Although butyrate also incr eased Na-K-ATPase protein expression twofold, the drug reduced the activity of the Na-K-ATPase by 55%. Our findings suggest that butyrate inhibits cAM P-stimulated Cl- secretion across MDCK cells in part by reducing the activi ty of the Na-K-ATPase.