UMLS:C0020538 - FACTA Search

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Query: UMLS:C0020538 (hypertension)
170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pseudohypoaldosteronism type 1 (PHA1, OMIM 264350) is a rare Mendelian disorder characterised by end-organ unresponsiveness to mineralocorticoids. Most steroid hormone insensitivity syndromes arise from mutations in the corresponding receptor, but available genetic evidence is against involvement of the mineralocorticoid receptor gene, MLR, in PHA1. A complete genome scan for PHA1 genes was undertaken using homozygosity mapping in 11 consanguineous families. Conclusive evidence of linkage with heterogeneity was obtained with a maximum two-locus admixture lod score of 9.9. The disease locus mapped to chromosome 16p12.2-13.11 in six families and to 12p13.1-pter in the other five families. The two chromosomal regions harbour genes for subunits of the amiloride-sensitive epithelial sodium channel: SCNN1B and SCNN1G on 16p and SCNN1A on 12p. Liddle's syndrome of hypertension and pseudoaldosteronism has been shown to arise from mutations in SCNN1B and SCNN1G. These results strongly suggest that PHA1 and Liddle's syndrome are allelic variants caused by mutations in genes encoding subunits of this sodium channel. These genes are of broad biological interest both in relation to sodium and water homeostasis in mammals and by virtue of their homology to the mec genes of Caenorhabditis elegans involved in mechanosensitivity and neuronal degeneration.
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PMID:Localisation of pseudohypoaldosteronism genes to chromosome 16p12.2-13.11 and 12p13.1-pter by homozygosity mapping. 882 86

Mineralocorticoids are adrenal steroid hormones that regulate the retention of sodium by the kidney and, hence, are crucial in the regulation of sodium balance, intravascular volume, and blood pressure. The molecular biology of mineralocorticoid biosynthesis and action has only recently been elucidated. The genes encoding the various enzymes that convert cholesterol to mineralocorticoids have now been cloned. This has revealed the molecular basis of several inherited forms of mineralocorticoid excess, which cause hypertension, and several forms of mineralocorticoid deficiency, which cause salt loss. The cloning of the mineralocorticoid receptor revealed a paradox. Both the mineralocorticoid and the glucocorticoid receptor are activated equally by cortisol, even though cortisol has very modest mineralocorticoid activity. This is explained by the cloning of two genes for the enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta HSD). Type-II 11 beta HSD, found primarily in the kidney, irreversibly converts cortisol to cortisone, which does not activate the mineralocorticoid receptor. Type-II 11 beta HSD thus defends the mineralocorticoid receptor from being activated by the very high concentrations of cortisol in the blood. Recent studies in genetically hypertensive rats suggest that other enzymes or factors that regulate salt balance may remain undiscovered. Thus the study of mineralocorticoid biosynthesis and action remains one of the most promising approaches to understanding hypertension.
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PMID:Molecular biology of mineralocorticoid metabolism. 883 34

Aldosterone, the most important mineralocorticoid, regulates electrolyte excretion and intravascular volume mainly through its effects on renal distal convoluted tubules and cortical collecting ducts. Excess secretion of aldosterone or other mineralocorticoids or abnormal sensitivity to mineralocorticoids may result in hypertension, suppressed plasma renin activity, and hypokalemia. Such conditions often have a genetic basis, and studies of these conditions have provided valuable insights into the normal and abnormal physiology of mineralocorticoid action. Deficiencies of steroid 11 beta-hydroxylase or 17 alpha-hydroxylase are types of congenital adrenal hyperplasia, the autosomal recessive inability to synthesize cortisol. These two defects often cause hypertension because of overproduction of cortisol precursors that are, or are metabolized to, mineralocorticoid agonists. These disorders result from mutations in the CYP11B1 and CYP17 genes encoding the corresponding enzymes. Glucocorticoid-suppressible hyperaldosteronism is an autosomal dominant form of hypertension in which aldosterone secretion is abnormally regulated by corticotropin. It is caused by recombinations between linked genes encoding closely related isozymes, 11 beta-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2), generating a dysregulated chimeric gene with aldosterone synthase activity. Apparent mineralocorticoid excess is a loss of functional ligand specificity of the mineralocorticoid receptor caused by a deficiency of the kidney isozyme of 11 beta-hydroxysteroid dehydrogenase, an enzyme that normally metabolizes cortisol to cortisone to prevent cortisol from occupying the receptor. This autosomal recessive form of severe hypertension results from mutations in the HSD11K (HSD11B2) gene.
Hypertension 1996 Dec
PMID:Inherited forms of mineralocorticoid hypertension. 895 79

We have previously reported that the Wistar/Furth (W/Fu) rat strain is resistant to mineralocorticoid hypertension. In the current study, we have examined renal mRNA levels for mineralocorticoid receptor (MR), glucocorticoid receptor (GR), renin and Na+, K(+)-ATPase in response to treatment with mineralocorticoids. Uninephrectomized male Wistar (WI) and W/Fu rats were treated with aldosterone or deoxycorticosterone acetate (DOCA) and were given 1% NaCl to drink. Rats were sacrificed after 1, 3 or 7 days of treatment. Renal MR and ATPase mRNA levels were significantly reduced in aldosterone and DOCA-treated WI rats (e.g. MR was 30% on day 3 and ATPase was 50% of control on day 7 of aldosterone treatment). Unexpectedly, GR mRNA levels paralleled the changes in MR. In W/Fu rats the level of message was either unchanged or only moderately altered by this treatment. In vivo administration of the MR antagonist RU28318 or the GR antagonist RU38486 to WI rats for 4 days reduced renal mRNA levels for both subunits of ATPase. In the W/Fu rat, this treatment resulted in no change in the alpha subunit and an increase in the beta subunit of ATPase. In preliminary studies, we have determined that the W/Fu rat is also resistant to dexamethasone-induced hypertension. These studies suggest that altered MR- and GR-mediated mechanisms may contribute to the resistance of the W/Fu rat strain to steroid-induced hypertension.
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PMID:The resistance of the Wistar/Furth rat strain to steroid hypertension. 896 28

Human epidemiological data show a strong association between low birth weight and hypertension in adulthood, an effect that has been ascribed to 'fetal programming'. In rats fetoplacental exposure to maternally administered dexamethasone throughout gestation reduces birth weight and produces hypertensive adult offspring, though the mechanism is unclear. Pre- and postnatal stress programmes hypothalamic-pituitary-adrenal (HPA) axis responses throughout the lifespan, an effect thought to be mediated via permanent effects on glucocorticoid receptor (GR) and/or mineralocorticoid receptor (MR) gene expression in the hippocampus. Corticosteroids also have specific central effects on blood pressure control mediated by GR and MR. This study investigated corticosterone (CORT) responses to restraint stress and GR and MR gene expression in areas of the brain postulated to mediate the central effects of corticosteroids on (i) HPA axis suppression (hippocampus), and (ii) blood pressure (organ vasculosum of the lamina terminalis (OVLT), sub-commissural organ, area postrema and nucleus tractus solitarius). Pregnant Wistar rats received dexamethasone (100 micrograms/kg.day-1) or vehicle on days 15-20 of gestation. This reduced birth weight by 11%. When the offspring were 16 weeks old, blood pressure was recorded directly and plasma CORT measured basally (AM) and after 30 min restraint. GR and MR mRNA expression were determined by in situ hybridization. Blood pressure was significantly elevated in the adult offspring of dexamethasone-treated pregnancies (dexamethasone 144 +/- 2/125 +/- 2 mm Hg vs. control 133 +/- 2.7/112 +/- 2.8 mm Hg; both p < 0.01). Offspring of dexamethasone-treated pregnancies had increased basal plasma CORT (155 +/- 29 nmol/l) compared to offspring of controls (79 +/-15 nmol/l, p < 0.05), but the CORT response to stress was similar. Hippocampal neuronal GR mRNA expression was significantly lower in the offspring of dexamethasone-treated pregnancies (dentate gyrus 20% lower, CA1 15% lower; p < 0.01). Similarly, hippocampal MR gene expression was decreased in CA1 and CA2 by 24 and 25%, respectively (p < 0.05). No differences in GR or MR mRNA expression were found in the OVLT, subcommissural organ, area postrema or nucleus tractus solitarius. These findings suggest that glucocorticoid excess in the last trimester of rat pregnancy (i) is sufficient to programme offspring hypertension; (ii) also increases basal plasma CORT levels, and (iii) permanently attenuates GR and MR mRNA expression in specific hippocampal subfields. Thus, if translated into protein, may reduce sensitivity to glucocorticoid feedback and thus contribute to the CORT excess. However, hypertension in this model is unlikely to be mediated by similar changes in GR or MR gene expression in the examined areas of the brain putatively involved in the more direct central regulation of blood pressure.
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PMID:Dexamethasone in the last week of pregnancy attenuates hippocampal glucocorticoid receptor gene expression and elevates blood pressure in the adult offspring in the rat. 899 73

The type 1 and type 2 isoforms of human 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) play a crucial role, respectively, in modulating glucocorticoid and mineralocorticoid hormone action. Deficiency of the 11 beta-HSD2 isoform, as described in the syndrome of apparent mineralocorticoid excess and following liquorice (glycyrrhetinic acid) or carbenoxolone ingestion, results in hypertension in which cortisol acts as a potent mineralocorticoid. Several studies have addressed the effects of progesterone, glycyrrhetinic acid, and their derivatives on 11 beta-HSD activity, but these were largely undertaken before the characterization of the 11 beta-HSD isoforms. The aim of this study was to evaluate the localization of 11 beta-HSD2 in human kidney and to study the effects of progesterone, glycyrrhetinic acid, and their related compounds on stable transfectants of the human 11 beta-HSD isoforms. Using an in-house sheep antibody against human 11 beta-HSD2, immunoperoxidase studies localized 11 beta-HSD2 to renal cortical and medullary collecting ducts. Glomeruli, vascular structures, loops of Henle, and proximal tubules were all negative. Confocal laser microscopy studies indicated both a cytoplasmic and nuclear localization for the enzyme within renal collecting ducts. The nuclear staining, which was intranuclear and was not associated with the nuclear membrane, accounted for 40% of the total cellular 11 beta-HSD2 immunoreactivity. Kinetic analysis of 11 beta-HSD activity in fetal kidney 293 cells stably transfected with h11 beta-HSD1/pcDNA3 or 11 beta-HSD2/pCR3, indicated, respectively, low-affinity dehydrogenase/oxoreductase activity (Km for F, 1.8 microM; Km for E, 270 nM) and high-affinity dehydrogenase activity (Km for F, 190 nM). The reductase activity of 11 beta-HSD1 was inhibited by 11 alpha-hydroxyprogesterone > carbenoxolone = glycyrrhetinic acid = progesterone > 11 beta-hydroxyprogesterone. The dehydrogenase activity of 11 beta-HSD2 was inhibited 11 alpha-hydroxyprogesterone = 11 beta-hydroxyprogesterone > glycyrrhetinic acid > carbenoxolone = progesterone. 11 beta-HSD2, expressed in the renal collecting duct, serves to protect the mineralocorticoid receptor (MR) in an autocrine fashion. The demonstration of a nuclear localization for what was thought to be principally a microsomal enzyme suggests that interaction between the MR and its ligand (either aldosterone or cortisol) may be a nuclear rather than a cytoplasmic event. The inhibitory effects of progesterone, glycyrrhetinic acid, and related compounds on 11 beta-HSD1 and 2 were similar, and it remains to be seen what implication these findings have for 11 beta-HSD1 action in tissues such as the liver and gonad and renal 11 beta-HSD2 activity in relation to sodium homeostasis and blood pressure control.
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PMID:Human 11 beta-hydroxysteroid dehydrogenase: studies on the stably transfected isoforms and localization of the type 2 isozyme within renal tissue. 902 19

We have reported that aldosterone is synthesized and cytochrome P450aldo mRNA exists in the vasculature. To clarify the pathophysiological role of vascular aldosterone in hypertension, we compared aldosterone production in the mesenteric arteries of stroke-prone spontaneously hypertensive rats (SHRSP) with that in Wistar-Kyoto rats (WKY). The expressions of mRNA of cytochrome P450aldo, mineralocorticoid receptor, and alpha 1, Na,K-ATPase in the mesenteric arteries were compared between the two groups. Aldosterone concentration in the perfusate of the vasculature was measured by radioimmunoassay after purification with high-performance liquid chromatography. Cytochrome P450aldo and mineralocorticoid receptor mRNA levels were quantified by Southern blot analysis of the products of reverse-transcribed polymerase chain reaction. Levels of alpha 1 Na,K-ATPase mRNA were measured by Northern blot analysis. Vascular aldosterone and cytochrome P450aldo mRNA levels of 2-week-old SHRSP were significantly increased compared with those of age-matched WKY. However, vascular aldosterone in 4- and 9-week-old SHRSP did not differ from that in age-matched WKY. Expression levels of mineralocorticoid receptor mRNA in the vasculature of 4- and 9-week-old SHRSP were significantly increased compared with those in age-matched WKY. Concentrations of vascular alpha 1 Na,K-ATPase mRNA of 2-, 4-, and 9-week-old SHRSP also were significantly higher than those in age-matched WKY. These results suggest that vascular aldosterone contributes to the pathophysiology of hypertension in SHRSP in the early stage.
Hypertension 1997 Jan
PMID:Vascular aldosterone in genetically hypertensive rats. 903 78

CONVERSION OF CORTISOL TO CORTISONE: 11 beta-Hydroxysteroid dehydrogenase (11 beta-HSD) is a microsomal enzyme complex which, in humans, catalyses the interconversion between biologically active cortisol and inactive cortisone. This prereceptor signalling mechanism is essential for maintaining the aldosterone selectivity of the intrinsically non-specific mineralocorticoid receptor and for modulating glucocorticoid access to the glucocorticoid receptor. Apparent mineralocorticoid excess (AME) is a syndrome of severe low-renin mineralocorticoid hypertension associated with marked hypokalaemia which arises from a congenital deficiency of 11 beta-HSD. In AME patients, therefore, it is cortisol and not aldosterone which behaves as a potent mineralocorticoid. ISOFORMS OF 11 BETA-HSD: Two isoforms of human 11 beta-HSD have now been characterized and cloned. The type 1 isoform (11 beta-HSD1) is a low-affinity reduced nicotinamide adenine dinucleotide phosphate (NADP) dependent dehydrogenase-oxoreductase which is expressed in predominantly glucocorticoid target tissues and the encoding sequence of which is normal in patients with AME. In contrast, the type 2 isoform (11 beta-HSD2) is a high-affinity NADP-dependent unidirectional dehydrogenase which is expressed in placenta and mineralocorticoid target tissues such as renal collecting ducts and distal colonic epithelia. Exon- and intron-specific polymerase chain reaction amplification of the 11 beta-HSD2 gene from genomic DNA from members of a consanguinous kindred with AME consistently revealed a single missense mutation (C1228T) in two affected sibs and twin stillbirths. This mutation in codon 374 of exon 5 of the 11 beta-HSD2 gene creates an inframe premature stop (TGA) and, as such, results in a truncated 11 beta-HSD2 protein lacking the carboxyl-terminal proline-rich 32 amino acids. In keeping with an autosomal recessive mode of inheritance, both parents were phenotypically and biochemically normal but were heterozygous for this mutation. Unique to this kindred were expression analyses of the native mutant 11 beta-HSD2 enzyme in the stillbirth-affected placenta, which was almost completely devoid of NADP-dependent 11 beta-dehydrogenase activity. Immunohistochemical and Western blot analyses revealed the absence of 11 beta-HSD2 protein using antisera raised against synthetic peptide sequences corresponding either to the carboxyl terminus or other domains of the enzyme. MISSENSE MUTATION: In this kindred with AME, congenital deficiency of 11 beta-HSD activity is due to a single missense mutation in exon 5 of the 11 beta-HSD2 gene. Simultaneous studies by two other groups have similarly revealed no gross deletions or rearrangements of the 11 beta-HSD2 gene, but have described a number of single point mutations and oligonucleotide deletions in exons 3, 4 and 5, and adjacent to a splice site in intron 3. Recombinant expression analysis of site-directed mutant 11 beta-HSD2 complementary DNA constructs suggests a correlation between the predicted severity of these mutations and the biochemical and clinical phenotype. AME AS A CAUSE OF HYPERTENSION: The mutations in the 11 beta-HSD2 gene, together with those currently being sought by us for other kindreds with AME, establishes AME as a monogenic cause of human hypertension and will provide insight into the structure-function relationships of this important enzyme.
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PMID:Human hypertension caused by mutations in the 11 beta-hydroxysteroid dehydrogenase gene: a molecular analysis of apparent mineralocorticoid excess. 912 Jun 78

Compared to the outbred Wistar rat strain, the Fawn-hooded rat strain has several characteristics which suggest that the Fawn-hooded strain is hyperaroused. Fawn-hooded rats exhibit more freezing behavior in response to stress, have an increased preference for alcohol, develop adult onset hypertension, and have elevated urinary catecholamine levels. We used quantitative in situ hybridization to investigate central components of the corticotropin releasing hormone (CRH), arginine vasopressin (AVP) and noradrenergic stress response and arousal systems in these rats. We also measured basal corticosterone levels and adrenal weights to assess tonic hypothalamic-pituitary-adrenal axis activity. Compared to Wistar rats, Fawn-hooded rats had significantly increased CRH mRNA in the central nucleus of the amygdala and reduced CRH mRNA in the paraventricular nucleus of the hypothalamus. Fawn-hooded rats also bad reduced AVP mRNA expression in the parvocellular cells of the hypothalamic paraventricular nucleus. There were no differences between strains in glucocorticoid receptor mRNA in the hippocampus or the paraventricular nucleus or in mineralocorticoid receptor mRNA in the hippocampus. There was also no difference between strains in tyrosine hydroxylase mRNA in the locus ceruleus. Finally, adrenal weights were significantly reduced in the Fawn-hooded rats while basal corticosterone levels were similar in the two strains, which suggests central hypoactivity of the hypothalamic-pituitary-adrenal axis in Fawn-hooded rats compared to Wistar rats. Increased CRH mRNA in the central nucleus of the amygdala and reduced tonic hypothalamic-pituitary-adrenal axis activity may play a role in the unique behavioral and physiological characteristics of Fawn-hooded rats.
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PMID:Increased mRNA for corticotrophin releasing hormone in the amygdala of fawn-hooded rats: a potential animal model of anxiety. 916 May 83

Several important advances have been made in the pathogenesis of mineralocorticoid induced hypertension. A hybrid gene was found to be responsible for glucocorticoid remediable hypertension. This extra gene contains fragments of 11-beta-hydroxylase and aldosterone synthase. The hybrid gene is the result of an unequal crossing-over of the two genes located in close proximity on chromosome 8, and leads to the production of aldosterone and the hybrid steroids 18-hydroxycortisol and 18-oxocortisol. These hybrid steroids are also detected in patients with aldosterone producing adenoma but not in patients with hyperaldosteronism due to bilateral adrenal hyperplasia. In Apparent "Mineralocorticoid Excess", inherited as an autosomal recessive disorder, an increased ratio of urinary cortisol metabolite to cortisone is diagnostic. The syndrome is due to a deficiency of the renal enzyme 11-beta-hydroxysteroid dehydrogenase type II, which protects the mineralocorticoid receptor against cortisol that binds to the mineralocorticoid receptor like aldosterone. Liddle's syndrome is a rare entity and due to a constitute activation of an aldosterone dependent protein which triggers the amiloride sensitive sodium channel in the kidney. This results in hypokalemic hypertension with suppressed aldosterone and renin levels.
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PMID:[Mineralocorticoid-induced hypertension]. 924 33

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