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)

The 11 beta-hydroxysteroid dehydrogenase type II enzyme (11 beta HSD2) converts cortisol into cortisone, thus preventing occupation of the non-selective mineralocorticoid receptor by glucocorticoids in the kidney. Placental 11 beta HSD2 is also thought to protect the fetus from the high maternal circulating levels of glucocorticoids. Mutations generating inactive enzymes have been described in the HSD11B2 gene in the congenital syndrome of apparent mineralocorticoid excess (AME)--a low renin form of hypertension. Recently, a mutation has been identified in a family with AME and in which there is a high incidence of stillbirths. In this study we have expressed the R374X mutation and show that the mutant is devoid of enzyme activity in intact mammalian cells expressing a significant level of the truncated protein. While this observation elucidates the cause of AME in this family the degree to which R374X also contributes to the higher incidence of failed pregnancies remains to be determined.
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PMID:Mutations in the 11 beta-hydroxysteroid dehydrogenase type II enzyme associated with hypertension and possibly stillbirth. 924 35

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

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

Low birth weight in combination with a large placenta predicts human hypertension. The pathophysiological link remains unclear, but glucocorticoid excess impairs fetal growth and leads to offspring hypertension. A key controller of fetal glucocorticoid exposure and local tissue availability is 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2). The activity of placental 11beta-HSD2 correlates with fetal growth in animals and humans. Ethanol abuse and smoking are known to retard fetal growth which may relate to altered glucocorticoid action or dynamics. This study has examined whether nicotine or ethanol modulate glucocorticoid action in the placenta or fetus by inhibiting 11beta-HSD2, using clonal cell cultures, freshly isolated dually perfused intact human placentas and placentas from in vivo treated rats. No significant effect on the activity of 11beta-HSD2 by pathophysiologically relevant nicotine or ethanol concentrations was observed. The mechanism of action of nicotine and ethanol relevant to reduced fetal growth requires further study.
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PMID:Lack of effect of nicotine or ethanol on the activity of 11beta-hydroxysteroid dehydrogenase type 2. 945 96

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

The 11 beta-hydroxysteroid dehydrogenase type II enzyme (11 beta HSD2) inactivates glucocorticoids in the kidney and thus prevents glucocorticoids from occupying the non-selective mineralocorticoid receptor in epithelial tissues. Mutations in the HSD11B2 gene have been found to cause the syndrome of apparent mineralocorticoid excess, a rare autosomal recessive disease characterized by severe hypertension. Thus, this locus could also be an ideal candidate involved in the etiology of primary hypertension. We identified a polymorphism in exon 3 characterized by a GAG to GAA transition at codon 178, with the loss of an Alu I restriction site and analysed it in an association study using end-stage renal disease patients, diabetic or essential hypertensive patients and control subjects. Two-hundred and eighty nine subjects and patients were analysed; the genotype was determined by amplification of genomic DNA and subsequent digestion with Alu I restriction enzyme. The prevalence of the Alu I allele was 8.6% in healthy control subjects (n = 116). This prevalence was lower (chi 2 P = 0.035 vs. controls) than the 18.0% in a group of renal transplant patients (n = 61). The corresponding values for patients with diabetes mellitus (n = 25), hypertension (n = 41) and patients on dialysis (n = 46) were 4.0%, 4.8% and 4.3%, respectively. There was no correlation between blood pressure and the marker in non-ESRD subjects. These data indicate the presence of a polymorphic marker in exon 3 of the HSD11B2 gene; this marker is associated with end-stage renal disease but not with essential hypertension in humans.
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PMID:A new polymorphic restriction site in the human 11 beta-hydroxysteroid dehydrogenase type 2 gene. 958 99

AME has been a crucial experiment of biology from which much has been learnt about corticosteroid hormone action and mineralocorticoid hypertension. 11 beta-HSD is an important pre-receptor pathway determining corticosteroid hormone action. Any tissue expressing 11 beta-HSD1 or 11 beta-HSD2 can clearly modulate glucocorticoid and mineralocorticoid action independent of circulating concentrations. A series of related enzymes operates in a similar fashion to determine hormone action for other members of the thyroid/steroid hormone receptor superfamily (e.g. 17 beta-HSD, 25-hydroxyvitamin D 1 alpha-hydroxylase, aromatase, 5'-deiodinase, 5 alpha-reductase). Endocrinologists have been obsessed with measuring the concentrations of a hormone in the circulation and making their decisions on the basis of these results, whether or not that hormone is involved in the pathogenesis of a disease process. Such an approach needs to be revised, with greater emphasis on considering the action of a hormone within a given tissue and, in turn, on the role of these enzymes in the pathogenesis of human disease.
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PMID:Cortisol, hypertension and obesity: the role of 11 beta-hydroxysteroid dehydrogenase. 959 34

Apparent mineralocorticoid excess (AME) is a genetic disorder causing pre- and postnatal growth failure, juvenile hypertension, hypokalemic metabolic alkalosis, and hyporeninemic hypoaldosteronism due to a deficiency of 11 beta-hydroxysteroid dehydrogenase type 2 enzyme activity (11 beta HSD2). The 11 beta HSD2 enzyme is responsible for the conversion of cortisol to the inactive metabolite cortisone and therefore protects the mineralocorticoid receptors from cortisol intoxication. Several homozygous mutations are associated with this potentially fatal disease. We have examined the phenotype, biochemical features, and genotype of 14 patients with AME. All of the patients had characteristic signs of a severe 11 beta HSD2 defect. Birth weights were significantly lower than those of their unaffected sibs. The patients were short, underweight, and hypertensive for age. Variable damage of one or more organs (kidneys, retina, heart, and central nervous system) was found in all of the patients except one. The follow-up studies of end-organ damage after 2-13 yr of treatment in six patients demonstrated significant improvement in all patients. The urinary metabolites of cortisol demonstrated an abnormal ratio with predominance of cortisol metabolites, i.e. tetrahydrocortisol plus 5 alpha-tetrahydrocortisol/tetrahydrocortisone was 6.7-33, whereas the normal ratio is 1.0. Infusion of [11-3H]cortisol resulted in little release of tritiated water, indicating the failure of the conversion of cortisol to cortisone. Thirteen mutations in the HSD11B2 gene have been previously published, and we report three new genetic mutations in two patients, one of whom was previously unreported. All of the patients had homozygous defects except one, who was a compound heterozygote. Our first case had one of the most severe mutations, resulting in the truncation of the enzyme 11 beta HSD2, and died at the age of 16 yr while receiving treatment. Three patients with identical homozygous mutations from different families had varying degrees of severity of clinical and biochemical features. Due to the small number of patients with identical mutations, it is difficult to correlate genotype with phenotype. In some cases, early and vigilant treatment of AME patients may prevent or improve the morbidity and mortality of end-organ damage such as renal or cardiovascular damage and retinopathy. The outcome of treatment in more patients may establish the efficacy of treatment.
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PMID:Examination of genotype and phenotype relationships in 14 patients with apparent mineralocorticoid excess. 966 90

The syndrome of apparent mineralocorticoid excess (AME) is a heritable form of hypertension in which cortisol acts as a potent mineralocorticoid. The type I variant results in a severe clinical and biochemical phenotype and arises because of mutations in the gene encoding the type 2 isozyme of 11beta-hydroxysteroid dehydrogenase (11beta-HSD2), an enzyme responsible for the peripheral inactivation of cortisol to cortisone. Only mild abnormalities of cortisol metabolism have been found in the type II variant of AME, suggesting that it may be a separate gene defect. In an extensive consanguineous Sardinian pedigree affected with "type II" AME, a novel homozygous point mutation (C945T) was found in the human 11beta-HSD2 gene in four affected individuals. Thirteen family members were heterozygous for the resultant R279C amino acid substitution. The LOD score of linkage of the mutation to the disease was 3.23. Expression of the 11beta-HSD2 mutant cDNA resulted in an enzyme with reduced maximum velocity, but similar substrate affinity, compared with activity of the wild-type cDNA. Affected individuals were >30 years of age and had both mineralocorticoid hypertension and evidence of impaired metabolism of cortisol to cortisone. The heterozygote state was phenotypically normal but was associated with subtle defects in cortisol metabolism. AME represents a spectrum of mineralocorticoid hypertension with severity reflecting the underlying genetic defect in the 11beta-HSD2 gene; classification into distinct subtypes is inappropriate. Hypertensive populations should be screened to identify the prevalence of milder defects in 11beta-HSD2 in patients currently labeled as having "essential" hypertension.
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PMID:Molecular basis for hypertension in the "type II variant" of apparent mineralocorticoid excess. 968 87


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