Estrogen negatively regulates the renal epithelial sodium channel (ENaC) by promoting Derlin-1 expression and AMPK activation

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.

Drug‐induced peripheral oedema: An aetiology‐based review

“…Arteriolar vasodilatation through 5-HT2 receptors inhibition [58][59][60] Antiepileptics Carbamazepine, 61 Baclofen 86 -increased capillary permeability especially with concomitant alcohol consumption 86 -GABAergic vasodilatation through central inhibition of sympathetic tone 87,88 -myogenic response inhibition through GABA A stimulation induced by loss of selectivity 89 Cytokines G-CSF, 90 interleukin 2, 91 interferon-α2b 36 Increased capillary permeability (as these drugs are responsible for capillary leak syndrome) Progestins 10 Sodium and water retention for progestins without anti-mineralocorticoid effect 106,107 Aromatase inhibitors: anastrozole, 108 letrozole, 108 exemestane 109 Sodium and water retention by removal of oestrogen-dependent ENaC receptors inhibition 110 SERM: tamoxifen 108,111 -sodium and water retention by removal of oestrogen-dependent ENaC receptors inhibition 110 -lymphedema through disturbance of lymphatic vasculature stability mediated by oestrogen receptors α 112…”

“…GnRH agonists: 108 gosereline, leuprolide Sodium and water retention by removal of oestrogen-dependent ENaC receptors inhibition 110 and through reduction of the antimineralocorticoid effect of progesterone 106,107 Antiandrogen: 99 abiraterone Sodium and water retention due to mineralocorticoid effect Anticortisolic: metapyrone 99 Sodium and water retention due to mineralocorticoid effect Insulin 113 -increased capillary permeability -arteriolar vasodilatation -sodium and water retention due to intrinsic antinatriuretic effect and through RAAS activation Growth hormone 114 Sodium and water retention through ENaC stimulation 115 Drugs for pulmonary arterial hypertension PGI 2 analogues/agonists: treprostinil, 116 selexipag 117 -increased capillary permeability -PGI 2 -dependent precapillary vasodilatation 118 Endothelin receptor antagonists: 119 ambrisentan, bosentan -precapillary arteriolar vasodilatation 119 -sodium and water retention through inhibition of natriuretic and aquaretic effects of ET B and ET A…”

A Genome-Wide Association Study of a Korean Population Identifies Genetic Susceptibility to Hypertension Based on Sex-Specific Differences

“…For example, estrogen can provide nitric oxide or superoxide products according to the conditions of vascular walls [57]. The main function of the epithelial sodium channel (ENaC) in the kidney distal nephron, which mediates sodium and water balance and the stabilization of blood pressure, is affected by estrogen effects of increasing ubiquitination [58]. These seem to support the results of the heterogeneity test.…”

Plasma creatine and incident type 2 diabetes in a general population‐based cohort: The PREVEND study

“…In our study, within the females, we found higher plasma creatine concentrations in females that were postmenopausal, as compared to premenopausal females. A potential explanation for the higher postmenopausal plasma creatine concentrations might be the fact that estrogens are able to activate AMP‐activated protein kinase (AMPK), which down‐regulates the creatine transporter in the proximal tubulus, leading to enhanced creatine excretion 51–53 …”