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)

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

It has been suggested that the association between the development of hypertension and a combination of low birth weight and high placental weight can be explained by variations in expression of NAD+-dependent 11beta-hydroxysteroid dehydrogenase (11-HSD2 or 11-HSD K) in the placenta. Enzymatic activity and mRNA levels of 11-HSD2 were measured in 111 human placentas taken from normal births. There were no correlations between either 11-HSD2 activity or mRNA levels and either fetal or placental weight. These studies suggest that variations in placental 11-HSD activity do not influence fetal or placental weight in humans.
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PMID:Variation in placental type 2 11beta-hydroxysteroid dehydrogenase activity is not related to birth weight or placental weight. 914 81

Vascular smooth muscle (VSM) contains a bidirectional isoform of 11beta-hydroxysteroid dehydrogenase (11beta-HSD), the enzyme that can metabolize endogenous glucocorticoids to their respective 11-dehydro derivatives. 11BetaOH-progesterone (11betaOH-P), a compound that can be produced in vivo, is as potent or more potent than licorice derivatives in inhibiting renal and hepatic 11beta-HSD. When studied in homogenates prepared from primary cultures of rat VSM, 11betaOH-P and its derivative, 11-keto-progesterone (11-keto-P), proved to be potent, directionally specific inhibitors of vascular 11beta-HSD. 11BetaOH-P selectively inhibited the forward dehydrogenase reaction (corticosterone-->11-dehydrocorticosterone), whereas 11-keto-P selectively blocked the reverse oxidoreductase reaction. To test the physiological effects, vascular rings were prepared from rat aorta. Rings were incubated in culture media containing either a submaximal concentration of corticosterone (10 nmol/L), 11-dehydrocorticosterone (100 nmol/L), 11betaOH-P (1 micromol/L), 11-keto-P (1 micromol/L), or a combination of glucocorticoid and inhibitor for 24 hours. After the 24-hour incubation, rings were briefly stimulated sequentially with phenylephrine (10 nmol/L to 1 micromol/L) and angiotensin II (1 micromol/L). The immediate contractile response in rings incubated with both corticosterone and 11betaOH-P was greater than in rings previously incubated with either the corticosterone or 11betaOH-P alone (eg, response to 100 nmol/L phenylephrine in milligrams of force, mean+/-SE: corticosterone, 728+/-56, n=9; 11betaOH-P, 325+/-105, n=4; both, 1132+/-122, n=8; corticosterone versus both, P<.01). In contrast, the immediate contractile responses to phenylephrine and to angiotensin II were attenuated in rings exposed previously to both 11-dehydrocorticosterone and 11-keto-P. Thus, 11betaOH-P and 11-keto-P (and possibly structurally similar compounds) alter the vascular effects of glucocorticoids and may play a role in glucocorticoid-induced hypertension.
Hypertension 1997 Sep
PMID:11BetaOH-progesterone affects vascular glucocorticoid metabolism and contractile response. 931 31

Dahl salt sensitive (Dahl-S) rats develop hypertension soon after birth. The cause of the increased salt-sensitivity in the Dahl-S rat is unknown. The mineralocorticoid specificity of the kidney receptor is conferred by the activity of 11beta-hydroxysteroid dehydrogenase (11beta-HSD). There are two isoforms of 11beta-HSD (11beta-HSD1 and 11beta-HSD2). Deficiency or inhibition of 11beta-HSD2 causes sodium retention and hypertension. In the present study we measured the activity of hepatic and kidney 11beta-HSD1 in Dahl-S and R rats before and after the development of hypertension. The activity of 11beta-HSD1 in the liver was lower in the Dahl-S rats at 6 weeks of age (S = 8.01 +/- 0.89 v R = 11.91 +/- 0.84 nmol/mg protein/10 min (P < .02) but there was no difference at 10 weeks. In contrast, 11beta-HSD1 in the kidney was not different at 6 weeks but it was significantly lower in the Dahl-S rats at 10 weeks (S = 0.91 +/- 0.04 v R = 1.12 +/- 0.01 nmol/mg protein/10 min (P < .001). Plasma renin concentration was lower at 6 (6w) and 10 weeks (10w) in the Dahl-S rats: S-6w = 4.2 +/- 0.4 versus R-6W = 6.3 +/- 0.8 ng angiotensin I (AI)/mL/h (P < .04) and S-10w = 6.4 +/- 0.7 versus R-10w = 10 +/- 0.9 ng AI/mL/h (P < .009). Plasma aldosterone and corticosterone were not different between the two strains. Systolic blood pressure (SBP) in the Dahl-S rats was 124 +/- 3 mm Hg at 6 weeks and 241 +/- 6 mm Hg at 10 weeks (P < .001). SBP in the Dahl-R rats was 113 +/- 5 mm Hg at 6 weeks and 143 +/- 4 mm Hg at 10 weeks. In conclusion, Dahl-S rats have lower hepatic 11beta-HSD1 activity at 6 weeks of age and lower kidney 11beta-HSD1 at 10 weeks of age compared with Dahl-R rats of the same age. These findings suggest that diminished activity of both liver and kidney 11beta-HSD1 may play a role in the salt sensitivity and development of hypertension in the Dahl-S rat.
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PMID:11Beta-hydroxysteroid dehydrogenase in the Dahl rat. 932 6

11Beta-hydroxysteroid dehydrogenases (11beta-HSD) catalyse the interconversion of active glucocorticoids (cortisol, corticosterone) and their inert 11-keto derivatives (cortisone, 11-dehydrocorticosterone). The type-2 isozyme (11beta-HSD-2) is a high-affinity dehydrogenase that catalyses the rapid inactivation of glucocorticoids, thus ensuring selective access of aldosterone to otherwise non-selective mineralocorticoid receptors in the distal nephron. Mutations of the gene encoding 11beta-HSD-2 are responsible for the syndrome of apparent mineralocorticoid excess, in which cortisol illicitly occupies mineralocorticoid receptors, causing hypertension and hypokalaemia. 11Beta-HSD-2 is also highly expressed in the placenta and mid-gestation fetus, where it may protect developing tissues from the often deleterious actions of glucocorticoids upon fetal growth and organ maturation. 11Beta-HSD-1 is probably an 11beta-reductase in vivo. Its function is obscure, but may amplify glucocorticoid action during the diurnal nadir, drawing upon the substantial circulating levels of 11-keto steroids. Both isozymes are regulated during ontogeny and by a series of hormonal and other factors. 11Beta-HSD provide an important control of glucocorticoid action at a cellular level, and may represent new targets for therapeutic intervention.
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PMID:Medical and physiological aspects of the 11beta-hydroxysteroid dehydrogenase system. 937 Mar 41

Apparent mineralocorticoid excess (AME) characterized by early-onset hypertension and hypokalemia is due to congenital deficiency of 11 beta-hydroxysteroid dehydrogenase (11 beta HSD). Two isoforms of human 11 beta HSD are known, and the type 2 isoform (11 beta HSD2) has been recently shown to be responsible for AME. In this study we have analyzed the 11 beta HSD2 gene of a Japanese patient with AME. PCR amplification and subsequent nucleotide sequencing of the 11 beta HSD2 gene from the patient and his family members revealed that the patient has a compound heterozygous mutation of this gene. In 1 allele, an undescribed single nucleotide transition in codon 208 in exon 3 resulted in a substitution of arginine to histidine (CGC to CAC: R208H). In the other allele, a deletion of 3 nucleotides in codons 337-338 in exon 5 resulted in a substitution of arginine to histidine and a deletion of tyrosine residue (CGCTAT to CAT: R337H, delta Y338), which has been previously shown to abolish 11 beta HSD2 enzyme activity. A chloramphenicol acetyltransferase assay-based expression study involving the mineralocorticoid receptor indicated that the novel R208H mutation eliminates the enzymatic activity of 11 beta HSD2. From the genetic analysis of 50 healthy subjects, the novel R208H mutation was unlikely to be due to polymorphism. Together, these results indicate that this patient is a compound heterozygote for the mutation in the 11 beta HSD2 gene (R208H and R337H, delta Y338) and that these mutations inactivate the 11 beta HSD2 function and give rise to clinically manifest AME.
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PMID:A new compound heterozygous mutation in the 11 beta-hydroxysteroid dehydrogenase type 2 gene in a case of apparent mineralocorticoid excess. 939 12

The aim of this study was to examine the role of endothelin-A (ET(A)) receptors in mediating the hypertension and renal injury associated with high salt intake in Dahl salt-sensitive (DS) rats. To achieve this goal, we examined the effects of chronic selective ET(A) antagonist (A-127722) treatment at a dose of 10 mg/kg/d on arterial pressure, renal function, and morphology in DS and Dahl salt-resistant (DR) rats placed on a high sodium (8% NaCl) diet (HSD) for 3 weeks. Placement of DS rats (n=13) on HSD for 3 weeks caused a progressive increase in systolic pressure (from 118+/-3 to 186+/-15 mm Hg). The increase in systolic pressure was significantly attenuated (from 125+/-4 to 167+/-12 mm Hg) in DS rats treated with A-127722 (n=13). Mean arterial pressure (MAP) measured directly at the end of the study was also significantly lower by 18 mm Hg (P<.02) in the DS rats treated with A-127722. The slope of the chronic pressure-natriuresis curve was shifted to the right in DS rats and to the left by chronic ET(A) receptor blockade in DS rats. The hypertension in DS rats was associated with marked proteinuria (from 4.1+/-1.1 to 74.3+/-5.3 mg/24 h/100 g body weight) that was significantly attenuated (from 5.7+/-1.2 to 55.2+/-6.5 mg/24 h/100 g body weight) in DS rats treated with A-127722. The percentage of glomeruli displaying fibrosis, hypercellularity, and hyalinization was also significantly reduced after treatment with A-127722 in DS rats. Arterial pressure, protein excretion, renal hemodynamics, and morphologic structure were not significantly changed in response to ET(A) receptor blockade in DR rats placed on HSD. These data indicate that endothelin-A receptor activation may play a role in the exacerbation of hypertension and development of renal injury in DS rats.
Hypertension 1998 Jan
PMID:Endothelin-A receptor antagonism attenuates the hypertension and renal injury in Dahl salt-sensitive rats. 945 35

11Beta-hydroxysteroid dehydrogenase (11beta-HSD) is expressed in vascular smooth muscle cells (VSMC) but has not been reported to be present in vascular endothelial cells. This enzyme assists in regulating the cellular concentration of active endogenous glucocorticoids (GCs). We have observed that endothelium intact rat aortic rings express message for both Type 1 and Type 2 11beta-HSD whereas primary cultures of VSMC express only mRNA for the Type I isoform. Since GCs diminish prostacyclin synthesis in endothelial cells, we hypothesized that 11beta-HSD is present in vascular endothelial cells. In primary cultures of rat aortic endothelial (RAE) cells, mRNA from both isoforms of 11beta-HSD could be detected by RT-PCR with higher levels of the Type 1 isoform. The oxo-reductase reaction "activating" 11-dehydro metabolites back to the parent steroid is the preferred enzyme direction (12:1 after a 120 minutes steroid incubation) in intact RAE cells. When RAE cells are grown in the presence of antisense oligonucleotides specific for Type 1 11beta-HSD, oxo-reductase activity is decreased by approximately 50% but the dehydrogenase reaction, which inactivates endogenous GCs and is characteristic of the Type 2 isoform, is unaffected. Thus endothelial cells appear to express both isoforms of 11beta-HSD; the Type 1 isoform dominates functioning in the oxo-reductase mode. Inhibition of the oxo-reductase reaction may lower the local concentrations of GC and indirectly allow for increased production of prostacyclin in endothelial cells.
Hypertension 1998 Jan
PMID:Localization of 2 11beta-OH steroid dehydrogenase isoforms in aortic endothelial cells. 945 45

The present study was designed to examine the effects of chronic fetal placental embolization on the expression of 11beta-hydroxysteroid dehydrogenase (11beta-HSD) types 1 and 2, the intracellular enzymes responsible for the metabolism of glucocorticoids. Twelve instrumented fetal sheep were randomly allocated on Day 110 (term = 147 days) to either a control (n = 6) or embolized (n = 6) group. Embolized fetuses received daily injections of nonradioactive microspheres into the abdominal aorta for 21 days to decrease arterial oxygen content by 40-50% of the pre-embolization values. At the end of the experiment, fetal liver and kidney tissues as well as placental cotyledons were collected, and tissue levels of 11beta-HSD mRNA and activity were determined by standard Northern blot analysis and radiometric conversion assay, respectively. There was a 44% reduction (p < 0.01) in the level of renal 11beta-HSD2 mRNA in the embolized group as compared with the control group. Moreover, this reduction in mRNA was carried through to 11beta-HSD2 protein, since there was a corresponding decrease in the level of 11beta-HSD2 activity (4.5+/-0.2 vs. 2.9+/-0.1 pmol/min per milligram protein, p < 0.01). In contrast, levels of both 11beta-HSD1 mRNA and activity in the fetal liver remained unchanged. Moreover, both 11beta-HSD types 1 and 2 mRNA and activity in the placenta were not altered by the fetal placental embolization. In conclusion, chronic hypoxemia selectively inhibits renal 11beta-HSD2 mRNA expression and enzyme activity in the ovine fetus, which may contribute, at least in part, to the mechanisms leading to fetal hypertension.
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PMID:Chronic hypoxemia selectively down-regulates 11beta-hydroxysteroid dehydrogenase type 2 gene expression in the fetal sheep kidney. 947 46

The presence of 11beta-hydroxysteroid dehydrogenase (11beta-HSD) activity in the kidney has been suggested to be important in the regulation of glucocorticoid-induced disorders of electrolyte balance and the control of blood pressure. To assess the possible effect of 11beta-HSD isoforms in diabetes-related hypertension, we measured the mean systolic blood pressure and the 11beta-HSD activity and mRNA levels for both 11beta-HSD1 and 11beta-HSD2 in the kidney of streptozotocin (STZ)-diabetic female rats. Three weeks after injection of STZ (65 mg/kg), the mean systolic blood pressure of diabetic rats was elevated 13.6% above that of normal rats (P<.01). The renal 11beta-HSD2 activity and level of mRNA expression were significantly decreased in diabetic rats (P<.01). However, the treatment of rats with STZ did not decrease the levels of renal 11beta-HSD1 activity and mRNA expression in diabetic rats. Insulin administered subcutaneously to diabetic rats for 2 weeks completely reversed the decrease in renal 11beta-HSD2 activity and gene expression and prevented the elevation in blood pressure in the diabetic rat. These results indicate that alteration of renal 11beta-HSD2 activity and gene expression may be primarily responsible for the changes in blood pressure of STZ-diabetic rats after early treatment with insulin.
Hypertension 1998 Mar
PMID:Gene expression of 11beta-hydroxysteroid dehydrogenase type 1 and type 2 in the kidneys of insulin-dependent diabetic rats. 949 77


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