Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Aldosterone acts in mineralocorticoid-sensitive cells by binding to the mineralocorticoid receptor (MR). Because the MR displays similar affinity for aldosterone and glucocorticoid hormones and because these latter hormones are 100- to 1000-fold more abundant than aldosterone in the plasma, mechanisms are required to avoid permanent illicit occupancy of MR by glucocorticoid hormones. The main mechanism of mineralocorticoid selectivity is enzymatic: the 11beta hydroxysteroid dehydrogenase (HSD2) metabolizes glucocorticoid hormones into derivatives with a low affinity for MR. The cell biology and regulation of HSD2 are reviewed in this article, as well as its implications in human hypertension. Other factors play a role in mineralocorticoid selectivity: the MR itself, the possibility to form homodimers (MR-MR), or heterodimers (with the glucocorticoid receptor). All of these cellular events participate to successive dynamic equilibriums, which allow fine tuning of transcriptional regulation of target genes, depending on the target tissue and the hormonal status.
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PMID:Mineralocorticoid selectivity: molecular and cellular aspects. 1076 68

Epidemiological studies in many distinct human populations have associated low weight or thinness at birth with a substantially increased risk of cardiovascular and metabolic disorders, including hypertension and insulin resistance/type 2 diabetes, in adult life. The concept of fetal "programming" has been advanced to explain this phenomenon. Prenatal glucocorticoid therapy reduces birthweight, and steroids are known to exert long-term organizational effects during specific "windows" of development. Therefore, we hypothesized that fetal overexposure to endogenous glucocorticoids might underpin the link between early life events and later disease. In rats, birthweight is reduced following prenatal exposure to the synthetic glucocorticoid dexamethasone, which readily crosses the placenta, or to carbenoxolone, which inhibits 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2), the physiological feto-placental "barrier" to endogenous glucocorticoids. Although the offspring regain the weight deficit by weaning, as adults they exhibit permanent hypertension, hyperglycemia, and increased hypothalamic-pituitary-adrenal axis activity. Moreover, physiological variations in placental 11beta-HSD2 activity near term correlate directly with fetal weight. In humans, 11beta-HSD2 gene mutations produce a low birthweight, and some studies show reduced placental 11beta-HSD2 activity in association with intrauterine growth retardation. Moreover, low birthweight babies have higher plasma cortisol levels throughout adult life, indicating that hypothalamic-pituitary-adrenal axis programming also occurs in humans. The molecular mechanisms of glucocorticoid programming are beginning to be unraveled and involve permanent and tissue-specific changes in the expression of key genes, notably of the glucocorticoid receptor itself. Thus, glucocorticoid programming may explain, in part, the association between fetal events and subsequent disorders in adult life.
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PMID:Glucocorticoids, 11beta-hydroxysteroid dehydrogenase, and fetal programming. 1076 76

Glucocorticoids may underlie the association between prenatal stress, low birth weight and adult stress-associated disorders, e.g. hypertension and type 2 diabetes, increased hypothalamic-pituitary-adrenal (HPA) activity and affective dysfunction. Normally, 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) rapidly inactivates glucocorticoids in placenta and many foetal tissues, thus acting as a 'barrier' to maternal steroids. We investigated the effect of inhibiting foeto-placental 11beta-HSD in rats, using carbenoxolone (CBX), on subsequent HPA activity and regulation and stress-induced behaviour in adult offspring. Pregnant Wistar rats were injected with CBX (12.5 mg s.c.) or vehicle daily throughout pregnancy. CBX treatment reduced birth weight. Adult offspring of CBX-treated dams had persistently reduced body weight, increased basal corticosterone (CORT) levels, increased corticotropin-releasing hormone (CRH) and reduced glucocorticoid receptor (GR) mRNA in the hypothalamic paraventricular nucleus, though hippocampal GR and mineralocorticoid receptor (MR) mRNA expression were unaltered. In addition, these animals showed less grooming and rearing in an open field and reduced immobility in a forced swim test, and had increased GR mRNA expression in the basolateral (BLA), central (CEA) and medial (MEA) nuclei of the amygdala, with unaltered MR mRNA. These data suggest that disturbance of the foeto-placental enzymatic barrier to maternal glucocorticoids reduces birth and body weight, and produces permanent alterations of the HPA axis and anxiety-like behaviour in aversive situations. The behavioural and HPA effects may reflect GR gene programming in amygdala and hypothalamus, respectively. Foetal overexposure to endogenous glucocorticoids (prenatal stress or reduced activity of foeto-placental 11beta-HSD) may represent a common link between the prenatal environment, foetal growth and adult neuroendocrine and affective disorders.
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PMID:Inhibition of 11beta-hydroxysteroid dehydrogenase, the foeto-placental barrier to maternal glucocorticoids, permanently programs amygdala GR mRNA expression and anxiety-like behaviour in the offspring. 1076 36

Glucocorticoids may underlie the association between low birth weight and adult disorders such as hypertension, type 2 diabetes and affective dysfunction. We investigated the behavioural and molecular consequences of two paradigms of prenatal dexamethasone administration in rats. Rats received dexamethasone (100 microg/kg per day) throughout pregnancy (DEX1-3), in the last third of pregnancy only (DEX3) or vehicle. Both dexamethasone treatments reduced birth weight, only DEX1-3 offspring had reduced body weight in adulthood. In adult offspring, both prenatal dexamethasone paradigms reduced exploratory behaviour in an open field. In contrast, only DEX3 reduced exploration in an elevated plus-maze and impaired behavioural responses and learning in a forced-swim test. This behavioural inhibition may reflect increased baseline corticotrophin-releasing hormone mRNA levels (30% higher) in the central nucleus of the amygdala in both dexamethasone-exposed groups. Adult DEX3 offspring also showed increased corticotrophin-releasing hormone mRNA with unaltered glucocorticoid receptor mRNA in the hypothalamic paraventricular nucleus and reduced hippocampal glucocorticoid- and mineralocorticoid receptor mRNA expression, suggesting reduced hippocampal sensitivity to glucocorticoid suppression of the stress axis. In contrast, DEX1-3 rats had no changes in hippocampal corticosteroid receptors, but showed increased mRNA levels for both receptors in the basolateral nucleus of the amygdala. From this data we suggest that prenatal glucocorticoid exposure programs behavioural inhibition perhaps via increased amygdalar corticotrophin-releasing hormone levels, while DEX3 also impairs coping and learning in aversive situations, possibly via altered hippocampal corticosteroid receptor levels. Overexposure to glucocorticoids, especially late in gestation, may explain the link between reduced early growth and adult affective dysfunction.
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PMID:Prenatal glucocorticoid programming of brain corticosteroid receptors and corticotrophin-releasing hormone: possible implications for behaviour. 1131 32

Considerable evidence suggests that diabetes mellitus and hypertension are influenced by genetic factors. Studies in humans have associated glucocorticoid receptor (GR) polymorphisms with high blood pressure, insulin sensitivity, body mass index, increased visceral fat, and variations in tissue-specific steroid sensitivity. The N363S polymorphism of the GR results in an asparagine to serine amino acid substitution in a modulatory region of the receptor. Phosphorylation of serine residues in this region has been shown to enhance transactivation of GR responsive genes. The aim of this study was to investigate the association between the 363S allele and risk factors for coronary heart disease and diabetes mellitus in a population of European origin living in the northeast of the United KINGDOM: Blood samples from 135 males and 240 females were characterized for 363 allele status. The overall frequency of the 363S allele was 3.0%, 23 heterozygotes (7 males and 16 females) but no 363S homozygotes were identified. The data show a significant association of the 363S allele with increased waist to hip ratio in males but not females. This allele was not associated with blood pressure, body mass index, serum cholesterol, triglycerides, low-density lipoprotein and high-density lipoprotein cholesterol levels, and glucose tolerance status. The results of this study suggest that this GR polymorphism may contribute to central obesity in men. Further studies are required to elucidate the properties of GR(363S) at a molecular level.
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PMID:The N363S polymorphism of the glucocorticoid receptor: potential contribution to central obesity in men and lack of association with other risk factors for coronary heart disease and diabetes mellitus. 1134 38

Glucocorticoid excess frequently results in obesity, insulin resistance, glucose intolerance, and hypertension and may be the product of altered glucocorticoid hormone action. Tissue sensitivity to glucocorticoid is regulated by the expression of glucocorticoid receptor isoforms (GRalpha and GRbeta) and 11beta-hydroxysteroid dehydrogenase type I (11betaHSD1)-mediated intracellular synthesis of active cortisol from inactive cortisone. We have analyzed the expression of GRalpha, GRbeta, and 11betaHSD1 and their hormonal regulation in skeletal myoblasts from men (n = 14) with contrasting levels of adiposity and insulin resistance. Immunohistochemical, Northern blot, and Western blot analysis indicated abundant expression of GRalpha and 11betaHSD1 under basal conditions. The apparent K(m) and maximum velocity for the conversion of cortisone to cortisol were 440 +/- 14 nmol/L and 75 +/- 7 pmol/mg protein.h and 437 +/- 16 nmol/L and 33 +/- 6 pmol/mg protein.h (mean +/- SEM; n = 4) in the presence and absence of 20% serum. Incubation of myoblasts with increasing concentrations of glucocorticoid (50-1000 nmol/L) resulted in a dose-dependent decline in GRalpha expression and a dose-dependent increase in GRbeta expression. 11betaHSD1 activity was sensitively up-regulated by increasing concentrations of glucocorticoid (50-1000 nmol/L: P < 0.05). Abolition of these effects by the GR antagonist, RU38486, indicates that regulation of GRalpha, GRbeta, and 11betaHSD1 expression is mediated exclusively by the GRalpha ligand-binding variant. In contrast, 11betaHSD1 was down-regulated by insulin (20-100 mU/mL: P < 0.01) in the presence of 20% serum, whereas incubation with insulin under serum-free conditions resulted in a dose-dependent increase in 11betaHSD1 activity (P < 0.05). Incubation with insulin-like growth factor I resulted in a similar pattern of 11betaHSD1 activity. Although neither testosterone nor androstenedione (5-200 nmol/L) affected 11betaHSD1 activity, incubation of myoblasts with dehydroepiandrosterone (500 nmol/L) resulted in a decline in 11betaHSD1 activity (P < 0.05). These data suggest that glucocorticoid hormone action in skeletal muscle is determined principally by autoregulation of GRalpha, GRbeta, and 11betaHSD1 expression by the ligand-binding GRalpha isoform. Additionally, insulin and insulin-like growth factor I regulation of 11betaHSD1 may represent a novel mechanism that maintains insulin sensitivity in skeletal muscle tissue by diminishing glucocorticoid antagonism of insulin action.
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PMID:Regulation of glucocorticoid receptor alpha and beta isoforms and type I 11beta-hydroxysteroid dehydrogenase expression in human skeletal muscle cells: a key role in the pathogenesis of insulin resistance? 1134 42

Cortisol resistance in man has been diagnosed only in a few cases and families sofar. Since the first description in 1976 only about 30 patients and mostly asymptomatic family members with cortisol resistance have been described. To date, the molecular basis has been characterized in eight patients. In seven cases, mutations in the hormone binding domain of the glucocorticoid receptor gene were responsible for the clinical manifestations of cortisol resistance, while in one patient a mutation in the DNA-binding domain was found. Reports of a significant prevalence of possible cortisol resistance in patients attending the endocrine clinic for hypokalemia, hypertension, acne, hirsutism and menstrual disorders invites endocrinologists to carry out a thorough investigation for cortisol resistance in such patients.
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PMID:Hereditary glucocorticoid resistance. 1135 88

Potential mechanisms underlying prenatal programming of hypertension in adult life were investigated using a rat model in which maternal protein intake was restricted to 9% vs. 18% casein (control) during pregnancy. Maternal low protein (MLP) offspring exhibit glucocorticoid-dependent raised systolic blood pressure throughout life (20-30 mm Hg above the control). To determine the molecular mechanisms underlying the role of alterations in glucocorticoid hormone action in the prenatal programming of hypertension in MLP offspring, tissues were analyzed for expression of the glucocorticoid receptor (GR), mineralocorticoid receptor (MR), 11betaHSD1, 11betaHSD2, and corticosteroid-responsive Na/K-adenosine triphosphatase alpha1 and beta1. GR protein (95 kDa) and messenger RNA (mRNA) expression in kidney, liver, lung, and brain was more than 2-fold greater in MLP vs. control offspring during fetal and neonatal life and was more than 3-fold higher during subsequent juvenile and adult life (P < 0.01). This was associated with increased levels of Na/K-adenosine triphosphatase alpha1- and beta1-subunit mRNA expression. Levels of MR gene expression remained unchanged. Exposure to the MLP diet also resulted in markedly reduced levels of 11betaHSD2 expression in the MLP placenta on days 14 and 20 of gestation (P < 0.001), underpinning similar effects on 11betaHSD2 enzyme activity that we reported previously. Levels were also markedly reduced in the kidney and adrenal of MLP offspring during fetal and postnatal life (P < 0.001). This programmed decline in 11betaHSD2 probably contributes to marked increases in glucocorticoid hormone action in these tissues and potentiates both GR- and MR-mediated induction of raised blood pressure. In contrast, levels of 11betaHSD1 mRNA expression in offspring central and peripheral tissues remained unchanged. In conclusion, we have demonstrated that mild protein restriction during pregnancy programs tissue-specific increases in glucocorticoid hormone action that are mediated by persistently elevated expression of GR and decreased expression of 11betaHSD2 during adult life. As glucocorticoids are potent regulators not only of fetal growth but also of blood pressure, our data suggest important potential molecular mechanisms contributing to the prenatal programming of hypertension by maternal undernutrition in the rat.
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PMID:The maternal diet during pregnancy programs altered expression of the glucocorticoid receptor and type 2 11beta-hydroxysteroid dehydrogenase: potential molecular mechanisms underlying the programming of hypertension in utero. 1141 3

Insulin resistance is a condition of central importance in a cluster of clinical disorders including diabetes mellitus, hypertension, dyslipidemia, central obesity and coronary heart disease. Despite its association with numerous health problems, the mechanism responsible for the development of this phenomenon remains to be established. A novel theory has proposed that insulin resistance in diabetes stems, at least in part, from enhanced free fatty acid (FFA) oxidation and/or excessive production of glucocorticoids (GCs). Several key predictions of this premise were subjected to experimental testing using streptozotocin (STZ)-treated rats as a model for insulin-dependent diabetes mellitus and euglycemic-hyperinsulinemic clamp technique for the in vivo measurement of insulin actions. Euglycemic clamp studies with an insulin infusion index of 5 mU/kg/min were used to measure endogenous glucose production (EGP), glucose infusion rate (GIR), glucose disposal rate (GDR) and skeletal muscle glucose utilization index (GUI). Post-absorptive basal EGP and plasma levels of glucose and free fatty acids (FFA) were elevated in the STZ diabetic rats compared to their corresponding control values. In contrast, hypoinsulinemia was evident in these animals. Steady-state GIR and GDR during euglycemic-hyperinsulinemic clamp were markedly decreased in the STZ diabetic rats. Similarly, insulin-mediated suppression of EGP and plasma FFA concentration was also impaired in these animals. GUI, a measure of 2-deoxyglucose (2-DG) uptake, was increased in response to insulin in the order of white gastrocnemus (WG), red gastrocnemus (RG), extensor digitorum longus and soleus muscles. This parallels the percentage of red fibers in these muscles. Diabetes interferes with insulin's ability to increase 2-DG uptake in all of the above muscles with the exception of WG. Nullification of the associated hyperlipidemic and hypercortisolemic states of diabetes with etomoxir (hyperlipidemic) and the glucocorticoid receptor blocker RU-486 (hypercortisolemic) ameliorated the diabetes-related impairment of the in vivo insulin action. Overall these results together with those garnered from the literature support the notion that hypercortisolemia and the enhancement of FFA oxidation are involved, at least in part, in the development of hepatic and skeletal muscle insulin resistance in poorly controlled type I diabetes.
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PMID:Co-administration of etomoxir and RU-486 mitigates insulin resistance in hepatic and muscular tissues of STZ-induced diabetic rats. 1160 76

It has been long recognised that the glucocorticoid administration to pregnant mammals (including humans) reduces offspring birth weight. Epidemiologically, low weight or thinness at birth is associated with an increased risk of cardiovascular and metabolic disorders in adult life. So, does fetal exposure to glucocorticoids produce such 'programming' of adult disorders? Here data are reviewed which show, in rodents and other model species, that antenatal exposure to glucocorticoids reduces offspring birth weight and produces permanent hypertension, hyperglycaemia, hyperinsulinaemia, altered behaviour and neuroendocrine responses throughout the lifespan. This occurs with exogenous (dexamethasone) or endogenous glucocorticoids, the latter achieved by inhibiting 11 beta-hydroxysteroid dehydrogenase type 2, the feto-placental enzymic barrier to maternal glucocorticoids. Processes underlying fetal programming include determination of the 'set point' of the hypothalamic-pituitary-adrenal axis and of tissue glucocorticoid receptor expression. Detailed molecular mechanisms are being dissected. Analogous stress axis hyperreactivity occurs in lower birth weight humans and may be an early manifestation and indicate approaches to manipulation or prevention of the phenotype.
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PMID:Glucocorticoid programming of the fetus; adult phenotypes and molecular mechanisms. 1173 95


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