Role of Estrogen Receptors in a Model of Dilutional Hyponatremia

Purpose: Hyponatremia is the most frequently occurring electrolyte disorder and independent risk factor for increased patient mortality. Dilutional hyponatremia in liver failure due to inappropriate arginine vasopressin (AVP) release can be studied using rodent bile-duct ligation (BDL) model. Our previous sex differences studies in BDL rats show compared to males, female and ovariectomized (OVX) BDL rats did not develop hyponatremia, AVP neuron activation, or increased plasma copeptin (CPP; a marker for AVP), compared to sham ligated females. Due to increased adrenal and circulating estradiol (E2) in OVX BDL rats, the role of E2 was unclear. Intracerebroventricular infusion of estrogen receptor (ER) antagonist, ICI 182,780 (ICI) in female BDL rats increased CPP concentration compared to controls. These data suggest ER involvement in prevention of hyponatremia in female BDL rats. However, ICI is also a G protein-coupled estrogen receptor 1 (GPER) agonist. We tested GPER expression within hypothalamo-neurohypophyseal system of female rats. Methods: Immunohistochemistry was performed on three separate sets of forebrain sections from adult female Sprague-Dawley rats. All sets processed for GPER, and the separate sets stained for either AVP, oxytocin (OXY), or glia fibrillary acidic protein (GFAP). Results: Co-localization of GPER+AVP and GPER+OXY was observed in neurohypophyseal neurons (GPER+AVP, 64.8% and GPER+OXY, 64.0%). GPER+GFAP co-localization was not observed. Conclusion: GPER is expressed on subset of AVP and OXY neurons and not astrocytes in hypothalamo-neurohypophyseal system of female rats. Future studies in BDL rats will provide further insight about sex differences in neurohypophyseal function.