Oestrogen upregulates the expression levels and functional activities of duodenal mucosal CFTR and SLC26A6

Abstract

What is the central question of this study? Duodenal ulcer is a common disease. A sex-based difference in the incidence of duodenal ulcer has long been observed clinically, but the cause is unclear. What is the main finding and its importance? Duodenal mucosal bicarbonate secretion is the most important protective factor in duodenal mucosa against acid-induced damage. The cystic fibrosis transmembrane conductance regulator (CFTR) and the solute-linked carrier 26 gene family A6 (SLC26A6) are two key bicarbonate transport proteins that mediate duodenal mucosal bicarbonate secretion. We demonstrate that endogenous oestrogen upregulates the expression levels and functional activities of duodenal mucosal CFTR and SLC26A6, which contributes to the sex difference in the prevalence of duodenal ulcer. The incidence of duodenal ulcer is markedly lower in women than men, but the cause of the sex difference is not clear. The cystic fibrosis transmembrane conductance regulator (CFTR) and the solute-linked carrier 26 gene family A6 (SLC26A6) are two key bicarbonate transport proteins that mediate duodenal mucosal bicarbonate secretion, which is an important protective factor against acid-induced duodenal injury. The aim of this study was to investigate the effect of oestrogen on the expressions and functional activities of CFTR and SLC26A6 in duodenal mucosa. We found that the expression levels of duodenal CFTR and SLC26A6 were markedly higher in young (20- to 30-year-old) women than in young men and old (60- to 70-year-old) women and men. The expression levels of CFTR and SLC26A6 in young women were markedly higher in preovulatory phases than in premenstrual phases, which was consistent with the changes of serum estradiol concentrations. Further results showed that duodenal CFTR and SLC26A6 expression levels in female mice were markedly decreased after ovariectomy, and supplementation with estradiol reversed the changes in CFTR and SLC26A6. 17β-Estradiol increased CFTR and SLC26A6 expression levels of human duodenocytes in experiments in vitro. Functional experiments showed that basal and forskolin- and prostaglandin E -stimulated duodenal bicarbonate secretion in ovariectomized mice was markedly decreased and, likewise, supplementation with 17β-estradiol reversed the changes. In conclusion, endogenous oestrogen upregulates the expressions and functional activities of CFTR and SLC26A6 in duodenal mucosa, which could contribute to protection of the duodenum and explain the sex difference in the prevalence of duodenal ulcer.

Estrogenic Modulation of Ionic Channels, Pumps and Exchangers in Airway Smooth Muscle

“…This was corroborated by E2 treatment of OVX rats that mimicked the results of OHSS and through measurement of CFTR activity in freshly isolated uterine epithelia [204]. In another study, CFTR expression was higher in women than in men in duodenal mucosa cells and in duodenocytes treated with E2 (1 nM) for 12 h, where a significant increase in expression mediated by ERα was observed [205]. This was also corroborated by measuring the activity of CFTR in OVX mice.…”

“…This was also corroborated by measuring the activity of CFTR in OVX mice. Forskolin (a CFTR activator) stimulation response was markedly decreased, and this effect was reverted with E2 supplementation [205]. Similarly, peritoneal epithelial cells of rats with induced OHSS showed CFTR upregulation, and this genomic effect was reproduced by E2 treatment in OVX rats [206].…”

Oxalate as a potent promoter of kidney stone formation

“…Felix Knauf et al ( 108 ) found that the expression of SLC26A6 decreased in the duodenum of CFTR gene-deficient mice, intestinal oxalate secretion decreased significantly, and the deficient mice exhibited hyperoxalemia and hyperoxaluria. Estradiol can up-regulate CFTR on the surface of intestinal mucosal cells to increase the expression of SLC26A6 and regulate oxalate transport ( 109 , 110 ). Therefore, CFTR may be an upstream protein of SLC26A6.…”

Gender differences in concentration of itraconazole and hydroxyitraconazole

“…Farmakokinetske polne razlike koje se odnose na resorpciju leka mogu se pripisati razlikama u nivou sekrecije želudačne kiseline, a pojedine studije navode da je ona niža kod žena [6], brzini pražnjenja sadržaja iz želuca, na šta imaju uticaj polni hormone [7], sastavu duodenalnog soka [8] (kod premenopauzalnih žena povećana sekrecija bikarbonata u duodenumu u odnosu na muškarce, takođe zbog uticaja polnih hormona), nivou ekspresije P-glikoproteina u tankom crevu. Mada bi se to moglo očekivati obzirom na to da su steroidni polni hormoni supstrati za P-glikoprotein [9], to u nekim istraživanjima nije potvrđeno [10].…”