Abstract
The main functions of the epithelial sodium channel (ENaC) in the kidney distal nephron are mediation of sodium and water balance and stabilization of blood pressure. Estrogen has important effects on sodium and water balance and on premenopausal blood pressure, but its role in the regulation of ENaC function is not fully understood. Female Sprague–Dawley rats were treated with 17β-estradiol for 6 weeks following bilateral ovariectomy. Plasma estrogen, aldosterone, creatinine, and electrolytes were analyzed, and α-ENaC and derlin-1 protein expression in the kidney was determined by immunohistochemistry and western blotting. The expression levels of α-ENaC, derlin-1, AMPK, and related molecules were also examined by western blotting and real-time PCR in cultured mouse renal collecting duct (mpkCCDc14) epithelial cells following estrogen treatment. Immunofluorescence and coimmunoprecipitation were performed to detect α-ENaC binding with derlin-1 and α-ENaC ubiquitination. The results demonstrated that the loss of estrogen elevated systolic blood pressure in ovariectomized (OVX) rats. OVX rat kidneys showed increased α-ENaC expression but decreased derlin-1 expression. In contrast, estrogen treatment decreased α-ENaC expression but increased derlin-1 expression in mpkCCDc14 cells. Moreover, estrogen induced α-ENaC ubiquitination by promoting the interaction of α-ENaC with derlin-1 and evoked phosphorylation of AMPK in mpkCCDc14 cells. Our study indicates that estrogen reduces ENaC expression and blood pressure in OVX rats through derlin-1 upregulation and AMPK activation.
Highlights
Hypertension is a major risk factor for cardiovascular disease and is the main factor for morbidity and mortality in postmenopausal women[1]
Systolic blood pressure (SBP) was significantly increased in OVX rats at 4 weeks and 6 weeks after OVX compared to sham rats (Fig. 1a)
Estrogen treatment significantly decreased the OVX-induced increase in SBP to levels comparable to those observed in nonoperated sham female rats (Fig. 1c)
Summary
Hypertension is a major risk factor for cardiovascular disease and is the main factor for morbidity and mortality in postmenopausal women[1]. The incidence of hypertension significantly increases to a rate that equals or surpasses that in males, suggesting that ovarian hormones protect premenopausal blood pressure[2,3]. Among the multiple mechanisms that have been proposed to explain hypertension in menopausal women, sex hormones have been shown to have important effects on the regulation of sodium and body fluids and on the increase in blood pressure in postmenopausal women associated with sodium and water retention[4]. The body maintains long-term stability of blood pressure by regulating water and sodium levels in the kidneys[5]. Sodium reabsorption in the distal nephron is mainly mediated by the renal epithelial sodium channel (ENaC), a sodium-selective ion channel comprising three homologous subunits (α, β, and γ), each composed of two membrane-spanning domains[6].
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