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1.
Medicine (Baltimore) ; 98(50): e18215, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31852079

RESUMO

BACKGROUND: The influence of genetic polymorphisms on the development of gestational hypertension (GH) is unclear. The aim of this study was to examine whether single-nucleotide polymorphisms (SNPs) of the nuclear receptor subfamily 3, group C, member 2 (NR3C2) genes, rs5522, rs2070951, rs5534, s2248038, and s9992256 are associated with GH in Han Chinese women. METHOD: Sanger sequencing was used to analyze the genotypes of rs5522, rs2070951, rs5534, rs2248038, and rs9992256 loci of the NR3C2 gene in 450 patients with GH and 450 healthy controls. RESULTS: The rs5522 dominant model (odds ratio [OR] = 1.30, 95% confidence interval [CI]: 1.13-1.47, P < .001) and the recessive model (OR = 1.64, 95% CI: 1.33-1.86, P < .001) had higher GH risk. The rs2070951 dominant model (OR = 1.18, 95% CI: 1.03-1.35, P = .02) had higher risk of GH, and the recessive model (OR = 1.09, 95% CI: 0.84-1.34, P = .55) was not significant for GH risk. The rs5534 dominant model (OR = 1.25, 95% CI: 1.09-1.43, P = .001) had a higher GH risk. The rs2248038 and rs9992256 sites were not significantly related to GH risk. Gene-gene interactions at the rs5522, rs2070951, and rs5534 loci affected GH risk (OR = 1.34, 95% CI: 1.12-1.64, P < .001). CONCLUSION: The SNPs of the NR3C2 gene rs5522, rs2070951, and rs5534 are associated with GH in Han Chinese women.


Assuntos
DNA/genética , Grupos Étnicos , Predisposição Genética para Doença , Hipertensão Induzida pela Gravidez/genética , Polimorfismo de Nucleotídeo Único , Receptores de Mineralocorticoides/genética , Adulto , Alelos , Feminino , Frequência do Gene , Genótipo , Humanos , Hipertensão Induzida pela Gravidez/etnologia , Hipertensão Induzida pela Gravidez/metabolismo , Incidência , Gravidez , Receptores de Mineralocorticoides/metabolismo , Estudos Retrospectivos , Adulto Jovem
2.
Anticancer Res ; 39(11): 5879-5890, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704812

RESUMO

BACKGROUND/AIM: The aim of the study was to investigate the prognostic role of androgen receptor (AR), mineralocorticoid receptor (MR) and glucocorticoid receptor ß (GRß) expression in HER-2 negative breast cancer patients. MATERIALS AND METHODS: The study population (n=152) was enriched with triple-negative breast cancers (TNBC) (n=96; 63.2%). The median follow-up time was 100 months. AR, MR and GRß immunocytochemical staining was compared with that of epithelial-mesenchymal transition (EMT) markers (vimentin, SIP1, ZEB1). RESULTS: High expression of cytoplasmic MR was associated with dismal local relapse-free survival (RR=13.923; 95%CI=1.071-181.045; p=0.044) in tumours with non-TNBC phenotype. AR and GRß were more frequently expressed in ER+/PR+/HER2- tumours, while cytoplasmic MR was more often expressed in TNBC tumours (for all, p<0.0005). GRß and AR were associated with decreased vimentin expression (p<0.005), indicating their association with attenuated EMT. CONCLUSION: Cytoplasmic MR expression is a strong predictor of local recurrence in non-metastatic breast cancer patients with non-TNBC tumour phenotype.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/classificação , Neoplasias da Mama/mortalidade , Citoplasma/metabolismo , Recidiva Local de Neoplasia/mortalidade , Receptores de Mineralocorticoides/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Feminino , Seguimentos , Humanos , Metástase Neoplásica , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Prognóstico , Receptor ErbB-2/metabolismo , Receptores Androgênicos/metabolismo , Receptores Estrogênicos/metabolismo , Receptores de Glucocorticoides/metabolismo , Receptores de Progesterona/metabolismo , Estudos Retrospectivos , Taxa de Sobrevida
3.
J Biochem Mol Toxicol ; 33(12): e22411, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31621980

RESUMO

To date, microRNA-4709 (miR-4709) has not been studied in colon adenocarcinoma (COAD) on the basis of experiments. In our study, we aimed to investigate the biological roles and clinical significance of miR-4709 in COAD. The expression difference between miR-4709 and NR3C2 was measured based on The Cancer Genome Atlas database and cells. Kaplan-Meier and logrank tests were applied to determine the overall survival (OS) differences according to the miR-4709 and NR3C2 expression levels. To measure whether the miR-4709 level was associated with COAD cell growth, migration, and invasion, we respectively conducted 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, wound healing, and transwell assays. A luciferase reporter assay was applied to confirm the relationship between miR-4709 and its predicted target. High expression of miR-4709 was found in COAD tissues and cells. The OS rate in the miR-4709 low expression group was significantly higher than that in the miR-4709 high expression group. Univariate and multivariate analyses exhibited that miR-4709 expression was an independent adverse prognostic factor. Exogenous miR-4709 overexpression promoted proliferation, migration, and invasion of LOVO and SW480 cells. Bioinformatics analysis and luciferase assay demonstrated that miR-4709 directly binds to the 3'-untranslated region of NR3C2. NR3C2 was lowly expressed in COAD and high expression of NR3C2 had a better prognosis compared with that in the low expression of NR3C2. Correlation analysis showed that there is a close association between the level of expression of NR3C2 and miR-4709. Accordingly, miR-4709 may function as an oncogene in COAD and provide a preclinical proof for candidate management to target new miR-4709-NR3C2 signaling for COAD therapy.


Assuntos
Adenocarcinoma/patologia , Neoplasias do Colo/patologia , MicroRNAs/metabolismo , Receptores de Mineralocorticoides/metabolismo , Regiões 3' não Traduzidas , Adenocarcinoma/metabolismo , Antagomirs , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Neoplasias do Colo/metabolismo , Regulação para Baixo , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Análise Multivariada , Invasividade Neoplásica , Oncogenes , Prognóstico , Taxa de Sobrevida , Transfecção
4.
G Ital Nefrol ; 36(4)2019 Jul 24.
Artigo em Italiano | MEDLINE | ID: mdl-31373464

RESUMO

Cardiovascular and renal diseases are one of the main health problems in all industrialized countries. Their incidence is constantly increasing due to the aging of the population and the greater prevalence of obesity and type 2 diabetes. Clinical evidence suggests that aldosterone and the activation of mineralocorticoid receptors (MR) have a role in the pathophysiology of cardiovascular and renal diseases. Moreover, clinical studies demonstrate the benefits of mineralocorticoid receptor antagonists (MRAs) on mortality and progression of heart and kidney disease. In addition to renal effects on body fluid homeostasis, aldosterone has multiple extrarenal effects including the induction of inflammation, vascular rigidity, collagen formation and stimulation of fibrosis. Given the fundamental role of MR activation in renal and cardiac fibrosis, effective and selective blocking of the signal with MRAs can be used in the clinical practice to prevent or slow down the progression of heart and kidney diseases. The aim of the present work is to review the role of MRAs in light of the new evidence as well as its potential use as an antifibrotic in chronic kidney disease (CKD). The initial clinical results suggest that MRAs are potentially useful in treating patients with chronic kidney disease, particularly in cases of diabetic nephropathy. We don't yet have efficacy and safety data on the progression of kidney disease up to the end stage (ESRD) and filling this gap represents an important target for future trials.


Assuntos
Aldosterona/fisiologia , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Insuficiência Renal Crônica/tratamento farmacológico , Líquidos Corporais/fisiologia , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/etiologia , Ensaios Clínicos como Assunto , Citocinas/metabolismo , Nefropatias Diabéticas/tratamento farmacológico , Eplerenona/uso terapêutico , Fibrose/etiologia , Coração/efeitos dos fármacos , Cardiopatias/etiologia , Homeostase , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Naftiridinas/uso terapêutico , Receptores de Mineralocorticoides/metabolismo , Espironolactona/uso terapêutico
5.
Int J Mol Sci ; 20(13)2019 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-31261892

RESUMO

BACKGROUND: Angiotensin II (Ang II), released by the renin-angiotensin-aldosterone system (RAAS), contributes to the modulatory role of the RAAS in adipose tissue dysfunction. Investigators have shown that inhibition of AngII improved adipose tissue function and insulin resistance in mice with metabolic syndrome. Heme Oxygenase-1 (HO-1), a potent antioxidant, has been demonstrated to improve oxidative stress and adipocyte phenotype. Molecular effects of high oxidative stress include suppression of sirtuin-1 (SIRT1), which is amenable to redox manipulations. The mechanisms involved, however, in these metabolic effects of the RAAS remain incompletely understood. HYPOTHESIS: We hypothesize that AngII-induced oxidative stress has the potential to suppress adipocyte SIRT1 via down regulation of HO-1. This effect of AngII will, in turn, upregulate mineralocorticoid receptor (MR). The induction of HO-1 will rescue SIRT1, hence improving oxidative stress and adipocyte phenotype. METHODS AND RESULTS: We examined the effect of AngII on lipid accumulation, oxidative stress, and inflammatory cytokines in mouse pre-adipocytes in the presence and absence of cobalt protoporphyrin (CoPP), HO-1 inducer, tin mesoporphyrin (SnMP), and HO-1 inhibitor. Our results show that treatment of mouse pre-adipocytes with AngII increased lipid accumulation, superoxide levels, inflammatory cytokine levels, interleukin-6 (IL-6) and tumor necrosis factor α (TNFα), and adiponectin levels. This effect was attenuated by HO-1 induction, which was further reversed by SnMP, suggesting HO-1 mediated improvement in adipocyte phenotype. AngII-treated pre-adipocytes also showed upregulated levels of MR and suppressed SIRT1 that was rescued by HO-1. Subsequent treatment with CoPP and SIRT1 siRNA in mouse pre-adipocytes increased lipid accumulation and fatty acid synthase (FAS) levels, suggesting that beneficial effects of HO-1 are mediated via SIRT1. CONCLUSION: Our study demonstrates for the first time that HO-1 has the ability to restore cellular redox, rescue SIRT1, and prevent AngII-induced impaired effects on adipocytes and the systemic metabolic profile.


Assuntos
Adipócitos/metabolismo , Angiotensina II/farmacologia , Heme Oxigenase (Desciclizante)/metabolismo , Estresse Oxidativo , Sirtuína 1/metabolismo , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Animais , Citocinas/metabolismo , Ácido Graxo Sintases/metabolismo , Heme Oxigenase (Desciclizante)/antagonistas & inibidores , Metabolismo dos Lipídeos , Camundongos , Receptores de Mineralocorticoides/metabolismo
6.
Rev Med Chil ; 147(4): 490-498, 2019 Apr.
Artigo em Espanhol | MEDLINE | ID: mdl-31344212

RESUMO

The renin-angiotensin-aldosterone system modulates volume, sodium and potassium homeostasis. In the setting of a high sodium diet, up to 30% of patients with hypertension have a low or suppressed renin and increased volume. This phenotype of low renin hypertension (LRH) is multifactorial and includes infrequent inherited genetic syndromes, milder phenotypes of classic diseases and environmental exposures. All these conditions have in common a higher cardiovascular risk mediated by the over activation of the mineralocorticoid receptor (MR), present not only in the kidney, but also in vasculature, myocardium and adipocytes. Consequently, the aim of LRH treatment goes beyond the control of blood pressure and requires antagonizing MR with specific pharmacologic agents, pursuing normalization of renin as a clinical objective. Due to the unusual evaluation of renin status by non-endocrinologists and lack of disease awareness, only a minority of hypertensive patients receive this pathophysiologically-driven treatment that should reduce cardiovascular outcomes.


Assuntos
Hipertensão/metabolismo , Hipertensão/terapia , Sistema Renina-Angiotensina/fisiologia , Aldosterona/metabolismo , Gerenciamento Clínico , Humanos , Hipertensão/fisiopatologia , Receptores de Mineralocorticoides/metabolismo , Renina/metabolismo
7.
Endocrinology ; 160(5): 1044-1056, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30980716

RESUMO

Mineralocorticoid and glucocorticoid receptors (MRs and GRs) constitute a functionally important dual receptor system detecting and transmitting circulating corticosteroid signals. High expression of MRs and GRs occurs in the same cells in the limbic system, the primary site of glucocorticoid action on cognition, behavior, and mood; however, modes of interaction between the receptors are poorly characterized. We used chromatin immunoprecipitation with nucleotide resolution using exonuclease digestion, unique barcode, and single ligation (ChIP-nexus) for high-resolution genome-wide characterization of MR and GR DNA binding profiles in neuroblastoma cells and demonstrate recruitment to highly similar DNA binding sites. Expressed MR or GR showed differential regulation of endogenous gene targets, including Syt2 and Ddc, whereas coexpression produced augmented transcriptional responses even when MRs were unable to bind DNA (MR-XDBD). ChIP confirmed that MR-XDBD could be tethered to chromatin by GR. Our data demonstrate that MR can interact at individual genomic DNA sites in multiple modes and suggest a role for MR in increasing the transcriptional response to glucocorticoids.


Assuntos
Glucocorticoides/farmacologia , Receptores de Glucocorticoides/metabolismo , Receptores de Mineralocorticoides/metabolismo , Transcrição Genética/efeitos dos fármacos , Animais , Sequência de Bases , Sítios de Ligação/genética , Linhagem Celular Tumoral , Imunoprecipitação da Cromatina , DNA/genética , DNA/metabolismo , Camundongos , Ligação Proteica , Interferência de RNA , Ratos , Receptores de Glucocorticoides/genética , Receptores de Mineralocorticoides/genética , Elementos de Resposta/genética
8.
Biochim Biophys Acta Mol Cell Res ; 1866(8): 1282-1297, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30935967

RESUMO

Fas-associated factor 1 (FAF1) was originally isolated as a Fas-associated factor and was subsequently found to interact with numerous other proteins that are involved in various cellular events including Fas-mediated apoptosis, nuclear factor (NF)-κB, Wnt/ß-catenin, and transforming growth factor (TGF)-ß signaling pathways, mineralocorticoid receptor (MR)-mediated transactivation, and ubiquitin-dependent processes. Herein, we defined two small ubiquitin-like modifier (SUMO)-interacting motifs (SIMs) within FAF1 and demonstrated to be crucial for transcriptional modulation of the MR. Our study demonstrated that the SIMs of FAF1 do not play a significant role in regulating its subcellular localization, Fas-mediated apoptosis, or NF-κB or Wnt/ß-catenin pathways. Remarkably, FAF1 interacts with the sumoylated MR and represses aldosterone-activated MR transactivation in a SIM-dependent manner. Moreover, silencing of endogenous FAF1 in cells resulted in an increase in the induction of MR target genes by aldosterone, indicating that FAF1 functions as an MR co-repressor. We further provide evidence to suggest that the mechanisms of FAF1/SIM-mediated MR transrepression involve inhibition of MR N/C interactions and promotion of MR polyubiquitination and degradation. Sumoylation has been linked to impacting of repressive properties on several transcription factors and cofactors. Our findings therefore provide mechanistic insights underlying SUMO-dependent transcriptional repression of the MR.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Receptores de Mineralocorticoides/metabolismo , Transcrição Genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Aldosterona/farmacologia , Motivos de Aminoácidos , Animais , Células COS , Células HEK293 , Células HeLa , Humanos , Transporte Proteico , Receptores de Mineralocorticoides/agonistas , Receptores de Mineralocorticoides/genética , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/genética , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/metabolismo , Sumoilação/efeitos dos fármacos , Sumoilação/genética
9.
Horm Behav ; 112: 54-64, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30953639

RESUMO

Sexual and social development is affected by a complex interplay between genetic makeup and the early-life rearing environment. While many rodent studies focused primarily on the detrimental effects of early-life stress, human literature suggests that genetic susceptibility may not be restricted to negative environments; it may also enhance the beneficial effects of positive rearing conditions. To examine this interaction in a controlled setting, heterozygous mineralocorticoid receptor knockout (MR+/-) mice and control litter mates were exposed to a limited nesting/bedding (LN, impoverished), standard nesting (SN, control) or communal nesting (CN, enriched) paradigm from postnatal day 2-9 (P2-P9). Offspring was monitored for puberty onset between P24-P36 and, in females, maternal care-giving (i.e. as F1) during adulthood, after which basal corticosterone was measured. Different home-cage environments resulted in profound differences in received maternal care and offspring body weight. In male offspring, LN resulted in delayed puberty onset that was mediated by body weight and unpredictability of maternal care received during early development. In female offspring, rearing condition did not significantly alter sexual maturation and had little effect on their own maternal care-giving behavior. Genotype did affect maternal care: female MR+/- offspring exhibited a less active nursing style and upregulated fragmentation during adulthood, irrespective of early life conditions. Basal corticosterone levels were highest in MR+/- mice with a background of LN. Overall, we found a gene-by-environment interaction with respect to basal corticosterone levels, but not for sexual maturation or maternal behavior.


Assuntos
Comportamento Materno/fisiologia , Receptores de Mineralocorticoides/genética , Maturidade Sexual , Meio Social , Animais , Corticosterona/metabolismo , Feminino , Interação Gene-Ambiente , Heterozigoto , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Comportamento de Nidação/fisiologia , Receptores de Mineralocorticoides/metabolismo , Maturidade Sexual/genética , Estresse Psicológico/genética , Estresse Psicológico/metabolismo , Estresse Psicológico/fisiopatologia
10.
Cell Mol Neurobiol ; 39(4): 471-472, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30941611

RESUMO

Steroids are complex molecules, exerting known and still unknown effects in the nervous system. Throughout this volume, the reader will find a wide spectrum of articles, giving an up-to-date account of the molecular, physiological, pharmacological, and clinical aspects of steroid action on the nervous system.


Assuntos
Sistema Nervoso/efeitos dos fármacos , Receptores de Glucocorticoides/metabolismo , Receptores de Mineralocorticoides/metabolismo , Esteroides/farmacologia , Animais , Humanos , Camundongos , Neuroproteção/efeitos dos fármacos
11.
Food Chem ; 289: 419-425, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-30955632

RESUMO

Surface plasmon resonance (SPR) analysis of the main components of liquorice was performed and a novel strong mineralocorticoid receptor (MR) agonist, namely liquiritinapioside (LA), whose the binding constant was 1.093 × 10-5 M, was reported. As a supplement, LA has been further demonstrated to have a strong MR binding capacity through competitive binding experiments (the enrichment factor of LA was 10.22%). This study also validated the activity of LA on H9c2 cells. The expression of collagen I and the results of Masson staining were used to determine the ability of this substance to cause H9c2 cell fibrosis. Moreover, western blotting was used to verify the mechanism of compound-induced myocardial fibrosis. Overall, the attained results showed that LA could induce the activation of the TGF-ß1/p38 MAPK signalling pathway through the MR to induce H9c2 cell fibrosis.


Assuntos
Glycyrrhiza/efeitos adversos , Glycyrrhiza/química , Mineralocorticoides , Receptores de Mineralocorticoides/agonistas , Animais , Linhagem Celular , China , Colágeno Tipo I/metabolismo , Fibrose , Flavanonas/efeitos adversos , Flavanonas/análise , Flavanonas/metabolismo , Glucosídeos/efeitos adversos , Glucosídeos/análise , Glucosídeos/metabolismo , Glycyrrhiza/metabolismo , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Miocárdio/patologia , Extratos Vegetais/química , Receptores de Mineralocorticoides/metabolismo , Transdução de Sinais/efeitos dos fármacos , Terpenos , Fator de Crescimento Transformador beta1/metabolismo
12.
Int J Mol Sci ; 20(7)2019 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-30934833

RESUMO

Mineralocorticoid receptor (MR)-mediated signaling in the brain has been suggested as a protective factor in the development of psychopathology, in particular mood disorders. We recently identified genomic loci at which either MR or the closely related glucocorticoid receptor (GR) binds selectively, and found members of the NeuroD transcription factor family to be specifically associated with MR-bound DNA in the rat hippocampus. We show here using forebrain-specific MR knockout mice that GR binding to MR/GR joint target loci is not affected in any major way in the absence of MR. Neurod2 binding was also independent of MR binding. Moreover, functional comparison with MyoD family members indicates that it is the chromatin remodeling aspect of NeuroD, rather than its direct stimulation of transcription, that is responsible for potentiation of MR-mediated transcription. These findings suggest that NeuroD acts in a permissive way to enhance MR-mediated transcription, and they argue against competition for DNA binding as a mechanism of MR- over GR-specific binding.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Receptores de Mineralocorticoides/metabolismo , Transdução de Sinais , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/química , Corticosterona/metabolismo , DNA/metabolismo , Células HEK293 , Hipocampo/metabolismo , Humanos , Masculino , Camundongos Knockout , Modelos Biológicos , Proteína MyoD/metabolismo , Proteínas do Tecido Nervoso/química , Ligação Proteica , Domínios Proteicos , Receptores de Glucocorticoides/metabolismo , Relação Estrutura-Atividade
13.
J Renin Angiotensin Aldosterone Syst ; 20(1): 1470320319827449, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30813831

RESUMO

INTRODUCTION:: AZD9977 is a novel mineralocorticoid receptor (MR) modulator, which in preclinical studies demonstrated organ protection without affecting aldosterone-regulated urinary electrolyte excretion. However, when tested in humans, using fludrocortisone as an MR agonist, AZD9977 exhibited similar effects on urinary Na+/K+ ratio as eplerenone. The aim of this study is to understand whether the contradictory results seen in rats and humans are due to the mineralocorticoid used. MATERIALS AND METHODS:: Rats were treated with single doses of AZD9977 or eplerenone in combination with either aldosterone or fludrocortisone. Urine was collected for five to six hours and total amounts excreted Na+ and K+ were assessed. RESULTS:: AZD9977 dose-dependently increased urinary Na+/K+ ratio in rats when tested against fludrocortisone, but not when tested against aldosterone. Eplerenone dose-dependently increased urinary Na+/K+ ratio when tested against fludrocortisone as well as aldosterone. CONCLUSIONS:: The data suggest that the contrasting effects of AZD9977 on urinary electrolyte excretion observed in rats and humans are due to the use of the synthetic mineralocorticoid fludrocortisone. Future clinical studies are required to confirm the reduced electrolyte effects of AZD9977 and the subsequent lower predicted hyperkalemia risk.


Assuntos
Aldosterona/farmacologia , Benzoatos/farmacologia , Fludrocortisona/farmacologia , Mineralocorticoides/farmacologia , Oxazinas/farmacologia , Receptores de Mineralocorticoides/metabolismo , Aldosterona/administração & dosagem , Animais , Benzoatos/administração & dosagem , Eplerenona/farmacologia , Fludrocortisona/administração & dosagem , Humanos , Oxazinas/administração & dosagem , Potássio/urina , Ratos , Sódio/urina
14.
Neuroscience ; 406: 268-277, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30880102

RESUMO

Photoperiod and diet are factors known to modulate the hypothalamic-pituitary-adrenal (HPA) axis. Specifically, shifts in photoperiod have been previously linked with affective and anxiety disorders. Furthermore, isoflavones have been shown to mediate behavioral outcome in response to the environment of the animal. Here, we investigated the effect of photoperiod alteration on the HPA axis and how the addition of isoflavones might modulate the response to stress. Male C57BL/6J mice were maintained on either a 12:12 or a 16:8 light-dark (LD) cycle for 10 days, and fed a diet of either standard rodent chow or an isoflavone free (IF) chow beginning 3 weeks prior to light alteration. Consistent with previous work, mice in the shorter active period (16:8 LD cycle) showed increased basal corticosterone (CORT) secretion. In the absence of isoflavones, this response was attenuated. Increases in mineralcorticoid (MR) and glucocorticoid (GR) receptor mRNA expression were seen in the pituitary following photoperiod alteration. However, animals fed the standard isoflavone rich chow showed increases in the ratio of MR:GR mRNA in the anterior bed nucleus of the stria terminalis following photoperiod alteration. Decreases in corticotrophin-releasing factor receptor 1 (CRFR1) mRNA expression were seen in animals fed the IF chow in the amygdala, prefrontal cortex and ventral hippocampus. These data suggest that alterations in CORT secretion following photoperiod alteration may be mediated through differences in CRFR1 gene expression or changes in MR:GR mRNA ratios. These findings provide insight into the potential mechanisms by which the HPA axis adapts to photoperiod and diet.


Assuntos
Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Isoflavonas/farmacologia , Fotoperíodo , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Hormônio Adrenocorticotrópico/metabolismo , Animais , Hormônio Liberador da Corticotropina/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Hipófise/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/metabolismo , Receptores de Glucocorticoides/metabolismo , Receptores de Mineralocorticoides/metabolismo , Estresse Psicológico/tratamento farmacológico
15.
Hypertension ; 73(4): 849-858, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30827147

RESUMO

Obesity is characterized by enhanced MR (mineralocorticoid receptor) activation, vascular stiffness, and associated cardiovascular and kidney disease. Consumption of a Western-style diet (WD), high in saturated fat and refined carbohydrates, by female mice, leads to obesity and vascular stiffening. Use of ECMR (endothelial cell-specific MR) knockout mice supports that ECMR activation is critical for development of vascular and cardiac fibrosis and stiffening. However, the role of ECMR activation in kidney inflammation and fibrosis remains unknown. We hypothesized that cell-specific deletion of ECMR would prevent WD-induced central aortic stiffness and protect the kidney from endothelial dysfunction and vascular stiffening. Four-week-old female ECMR KO and wild-type mice were fed either mouse chow or WD for 16 weeks. WD feeding increased body weight and fat mass, proteinuria, as well as vascular stiffness indices (pulse wave velocity and kidney artery stiffening) and impaired endothelial-dependent vasodilatation without blood pressure changes. The WD-induced kidney arterial stiffening was associated with attenuated eNOS (endothelial NO synthase) activation, increased oxidative stress, proinflammatory immune responses, alterations in extracellular matrix degradation pathways, and fibrosis. ECMR deletion prevented these abnormalities by improving eNOS activation and reducing macrophage proinflammatory M1 polarization, expression of TG2 (transglutaminase 2), and MMP (matrix metalloproteinase)-9. Our data support the concept that ECMR activation contributes to endothelial dysfunction, increased kidney artery fibrosis/stiffening, and impaired NOS (NO synthase) activation, processes associated with macrophage infiltration and polarization, inflammation, and oxidative stress, collectively resulting in tubulointerstitial fibrosis in females consuming a WD.


Assuntos
Endotélio Vascular/metabolismo , Nefropatias/patologia , Obesidade/fisiopatologia , Receptores de Mineralocorticoides/metabolismo , Artéria Renal/patologia , Rigidez Vascular/fisiologia , Vasodilatação/fisiologia , Animais , Dieta Ocidental/efeitos adversos , Endotélio Vascular/fisiopatologia , Feminino , Fibrose/metabolismo , Fibrose/patologia , Nefropatias/etiologia , Nefropatias/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/complicações , Obesidade/metabolismo , Estresse Oxidativo , Artéria Renal/metabolismo , Artéria Renal/fisiopatologia
16.
Drugs ; 79(4): 477-481, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30806972

RESUMO

Esaxerenone (MINNEBRO™)-a novel oral, non-steroidal, selective mineralocorticoid receptor blocker-is being developed by Daiichi Sankyo for the treatment of hypertension and diabetic nephropathies. In January 2019, based on positive results from a phase III trial conducted in Japan in patients with essential hypertension, esaxerenone received marketing approval in Japan for the treatment of hypertension. This article summarizes the milestones in the development of esaxerenone leading to this first global approval for the treatment of hypertension.


Assuntos
Nefropatias Diabéticas/tratamento farmacológico , Hipertensão/tratamento farmacológico , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Pirróis/uso terapêutico , Sulfonas/uso terapêutico , Ensaios Clínicos Fase III como Assunto , Aprovação de Drogas , Humanos , Japão , Antagonistas de Receptores de Mineralocorticoides/efeitos adversos , Estrutura Molecular , Pirróis/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptores de Mineralocorticoides/metabolismo , Sulfonas/efeitos adversos
17.
Vitam Horm ; 109: 133-149, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30678853

RESUMO

Encouraging changes in the steroid hormone receptor field from initially questioning the role of non-genomic actions of steroid hormones to acceptance of the concept that the acute, membrane-centric actions are linked and/or regulate the nuclear actions. The focus of this chapter is how the non-genomic effects are linked to the longer lasting, genomic actions of aldosterone. By non-genomic we refer to the rapid actions that occur within minutes do not require transcription or translation and occur in both classical MR target organs (kidney and colon) and non-epithelial tissues (blood vessels, heart, and adipose). The mechanism of rapid non-genomic actions of aldosterone varies between tissues. As a result, this chapter is viewed through the lens of how the non-genomic and genomic actions of aldosterone are linked in cardiovascular disease. Specifically, regulation of sodium flux in the myocardium has an important role in pathogenesis of cardiac arrhythmia. Since there are now recognized gender differences in cardiovascular disease, we also include preliminary studies to investigate the interaction of sex steroid hormones with the ligand binding pocket of the mineralocorticoid receptor. Overall, we aim to showcase how the non-genomic effects of aldosterone potentially modulate the genomic effects and represent additional targets for intervention.


Assuntos
Aldosterona/metabolismo , Transdução de Sinais/fisiologia , Animais , Feminino , Hormônios Esteroides Gonadais/metabolismo , Humanos , Masculino , Receptores Acoplados a Proteínas-G , Receptores de Mineralocorticoides/metabolismo , Fatores Sexuais
18.
Vitam Horm ; 109: 151-188, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30678854

RESUMO

Two mineralocorticoid receptor antagonists, spironolactone and eplerenone, are currently approved by the FDA. Several non-steroid based ligands are in clinical trials for indications including heart failure, hypertension and diabetic kidney disease, and even more structurally distinct chemical series are reported in the literature with preclinical data from animal models. Design of new ligands that are both selective over the other oxosteroid receptors (GR, PR and AR) and possess properties compatible with oral dosing, despite the overall lipophilic binding pocket of MR, remains a challenge. High-throughput screening has been successfully used to identify novel starting points in several drug discovery programs, and these were optimized using property based drug design, often aided by protein-ligand X-ray complex structures.


Assuntos
Anti-Hipertensivos/farmacologia , Hipertensão/tratamento farmacológico , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Receptores de Mineralocorticoides/metabolismo , Aldosterona/química , Aldosterona/metabolismo , Aldosterona/farmacologia , Animais , Anti-Hipertensivos/química , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Antagonistas de Receptores de Mineralocorticoides/química , Estrutura Molecular
19.
Vitam Horm ; 109: 17-36, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30678855

RESUMO

The mineralocorticoid receptor (MR) and its kin, the glucocorticoid receptor (GR) evolved from an ancestral corticoid receptor (CR) in a cyclostome (jawless fish) through gene duplication and divergence. Distinct MR and GR orthologs first appear in cartilaginous fishes, such as sharks, skates, rays and chimaeras. Although aldosterone, the main physiological mineralocorticoid in humans and other terrestrial vertebrates, is not synthesized by cyclostomes or cartilaginous fishes, cyclostome CR and cartilaginous fish MR and GR are activated by aldosterone. Aldosterone first appears in lungfish, lobe-finned fish that are forerunners of terrestrial vertebrates. Further sequence divergence of the MR and GR in terrestrial vertebrates led to emergence of aldosterone as a selective ligand for the MR. Interestingly, ray-finned fish do not synthesize aldosterone, leaving the identity of their physiological mineralocorticoid(s) unresolved. Several steroids: cortisol, 11-deoxycortisol, corticosterone, 11-deoxycorticosterone and progesterone activate fish MR and are potential mineralocorticoids in ray-finned fish. Here we review the evolution of the MR in cartilaginous fish, terrestrial vertebrates and ray-finned fish, and discuss new insights into progesterone activation of the MR in ray-finned fish.


Assuntos
Aldosterona/metabolismo , Evolução Molecular , Receptores de Mineralocorticoides/genética , Receptores de Mineralocorticoides/metabolismo , Vertebrados/fisiologia , Aldosterona/genética , Animais , Regulação da Expressão Gênica , Vertebrados/genética
20.
Vitam Horm ; 109: 189-209, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30678856

RESUMO

Mineralocorticoid receptor (MR) has been recently identified in adipose tissue, where its excessive activation contributes to several metabolic derangements often observed in obesity and metabolic syndrome. Recent findings support the existence of a bidirectional cross-talk between adipose tissue and adrenal glands, contributing to obesity-related hyperaldosteronism and subsequent adipocyte MR excessive activation. In this regard, MR pharmacological blockade has led to prevention of weight gain and metabolic benefits in murine models of genetic or diet-induced obesity. However, there is still a lack of knowledge on the potential metabolic effects of MR antagonists in clinical settings. Hence, larger clinical studies are deemed necessary to clarify the role of MR antagonism in obesity and metabolic syndrome in humans.


Assuntos
Adipócitos/metabolismo , Aldosterona/metabolismo , Receptores de Mineralocorticoides/metabolismo , Animais , Citocromo P-450 CYP11B2/antagonistas & inibidores , Regulação da Expressão Gênica/fisiologia , Antagonistas de Receptores de Mineralocorticoides , Receptores de Mineralocorticoides/genética
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