Estrogen-dependent regulation of sodium/hydrogen exchanger-3 (NHE3) expression via estrogen receptor β in proximal colon of pregnant mice

Although constipation is very common during pregnancy, the exact mechanism is unknown. We hypothesized that the involvement of estrogen receptor (ER) in the regulation of electrolyte transporter in the colon leads to constipation. In this study, the intestines of normal female ICR mouse and pregnant mice were examined for the expression of ER alpha and ER beta by immunohistochemistry and in situ hybridization. ER beta, but not ER alpha, was expressed in surface epithelial cells of the proximal, but not distal, colon on pregnancy days 10, 15, and 18, but not day 5, and the number of ER beta-positive cells increased significantly during pregnancy. Expression of NHE3, the gene that harbors estrogen response element, examined by immunohistochemistry and western blotting, was localized in the surface epithelial cells of the proximal colon and increased in parallel with ER beta expression. In ovariectomized mice, NHE3 expression was only marginal and was up-regulated after treatment with 17 beta-estradiol (E-2), but not E-2 + ICI 182,780 (estrogen receptor antagonist). Moreover, knock-down of ER beta expression by electroporetically transfected siRNA resulted in a signiWcant reduction of NHE3 expression. These results indicate that ER beta regulates the expression of NHE3 in the proximal colon of pregnant mice through estrogen action, suggesting the involvement of increased sodium absorption by up-regulated NHE3 in constipation during pregnancy.