Regulatory mechanism underlying cyclic changes in mouse uterine bicarbonate secretion: role of estrogen

Abstract

Our previous study has demonstrated that bicarbonate in the uterine fluid plays an indispensable role in sperm capacitation. However, the cellular mechanisms underlying the formation of bicarbonate-rich uterine fluid and the regulatory mechanism remained largely unknown. In this study, the expression profiles of bicarbonate transport/production proteins, the cystic fibrosis transmembrane conductance regulator (CFTR), SLC26A6, carbonic anhydrase 2 (CAR2, CA2) and CAR12 (CA12), throughout the estrous cycle, were examined in the mouse uterus by western blot. The results showed that the maximum expression levels of the proteins examined were observed at estrus. Luminal surface pH measurements showed that the resting uterine surface pH at estrus was significantly higher than that at diestrus, which could be reduced significantly by CFTR blocker, diphenylamine-2,2 0 -dicarboxylic acid, SLC26A6 inhibitor, 4 0 ,4 0 -diisothiocyanostilbene-2 0 ,2 0 -disulfonic acid, and CA inhibitor, acetazolamide. In ovariectomized mice and primary culture of endometrial epithelial cells, estrogen could upregulate CFTR, SLC26A6, CAR2, and CAR12 expression with a corresponding increase in the bicarbonate-dependent short-circuit current (I sc ) and endometrial surface pH. The present results have demonstrated dynamic changes in uterine bicarbonate secretion and expression of the proteins involved in bicarbonate secretion during the estrous cycle and suggested a novel role of estrogen in regulating uterine bicarbonate transport, which may be important for successful reproduction.Reproduction (2010) 140 903-910

Abnormally enhanced cystic fibrosis transmembrane conductance regulator-mediated apoptosis in endometrial cells contributes to impaired embryo implantation in controlled ovarian hyperstimulation

“…In fact, we have demonstrated that ectopic high concentration of E 2 (10 mg/mL) dramatically induced apoptosis in cultured endometrial epithelial cells, which can be completely abolished by the CFTR inhibitor, indicating that CFTR mediates supraphysiologic E 2 -induced apoptosis in the endometrial epithelial cells. On the other hand, recent studies into the role of CFTR in female reproductive health and disease have made it clear that CFTR plays a key role in regulating female sex hormone responsive fluid volume and composition, and that aberrant upregulation of CFTR expression by high concentrations of E 2 may lead to disturbance of the fluid environment resulting in various pathological conditions (18,19,43,44). To our surprise, we did not observe significant ovarian fluid accumulation during implantation in the COH model.…”

“…In addition to its wellestablished ion channel function, CFTR has been proposed to have many other roles that either directly or indirectly impact various cellular functions, including apoptosis (13,14). Previous studies from both our laboratory and that of other investigators have revealed that the expression of uterine CFTR changes with the estrous cycle (15)(16)(17)(18)(19). In addition, stimulation of CFTR expression by estrogen (E) both in vivo and in vitro (20,21) has also been demonstrated and down-regulation of CFTR by P reported (22).…”

Emerging role of cystic fibrosis transmembrane conductance regulator as an epigenetic regulator: linking environmental cues to microRNAs

“…Studies on both rodents and humans have revealed that the expression of CFTR in the female reproductive tract is enhanced by oestrogens and suppressed by progesterone in vitro or in vivo. 23,[103][104][105][106][107][108][109] In airway cells, b-oestradiol was found to promote CFTR protein maturation by upregulating the CFTR-interacting protein Na + /H + exchanger regulatory factor (NHERF) 1. 110 A recent study using nucleosome mapping across the CFTR locus identified the glucocorticoid receptor as a trans-acting factor regulating CFTR transcription.…”

Ion channels/transporters as epigenetic regulators? —a microRNA perspective

“…Furthermore, CFTR is also known to be involved in bicarbonate transport either directly [53] or indirectly [54], which is important for activation of cAMPdependent signaling pathway [53,55] in addition to pH regulation. In the last decade, various studies from our laboratory have demonstrated that normal function of CFTR and/or ENaC is critical for a variety of reproductive events such as sperm capacitation [53,56] and implantation [57,58], defects or dysregulation of which lead to a number of pathological conditions, such as ovarian hyperstimulation syndromes, hydrosalpinx and infertility [44,59]. These observations suggest that ion channels/transporters may respond to microenvironmental changes and play an important role in various physiological and pathological processes.…”