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 HSD11B2 and VPATPD genes encoding the human kidney isozyme of 11beta-hydroxysteroid dehydrogenase (11-HSD2) and subunit D of the vacuolar proton ATPase, respectively, are located on chromosome 16q22. They are transcribed from complementary DNA strands and their 3' ends are only 0.5 kilobase apart. Because polymorphisms in HSD11B2 have been associated with hypertension and salt sensitivity, we characterized the human VPATPD gene. It spans 19 kb and consists of 8 exons. The encoded protein is 99.5% identical to mouse subunit D at the amino acid level. An alternating purine-pyrimidine tract is located in the 3'-untranslated region of VPATPD. On genotyping 17 hypertensive subjects, no length polymorphism was found. Although VPATPD and HSD11B2 are both expressed in kidney and placenta, they are regulated differently; forskolin upregulates HSD11B2 but not VPATPD in human choriocarcinoma JEG3 cells. The functional significance of the proximity of these two genes remains to be established.
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PMID:Structure of the VPATPD gene encoding subunit D of the human vacuolar proton ATPase. 1111 22

Recent advances in genetic determination of human essential hypertension (EHT) are discussed by reviewing the candidate genes. Candidate genes have been selected based on genetic information from classical linkage analysis (affected sib-pair analysis) or mendelian hypertension (autosomal dominant inheritance of hypertension). Most of these genes are, directly or indirectly, coupled to salt handling of the kidney, being included in the renin-angiotensin system (RAS), steroid-hormone metabolism, and renal sodium transporters. Angiotensinogen (AGT) gene in RAS was first described as a strong candidate associated with the onset of hypertension, since sib-pair linkage analysis has demonstrated the trait loci for hypertension which includes the coding region for AGT. M235T polymorphism of AGT has been studied extensively in many populations including Japanese, and the results suggest a weak, but significant linkage with hypertension. The presence (insertion [I]) or absence (deletion [D]) of 287bp in intron 16 of angiotensin converting enzyme gene has also been examined in RAS, and the results suggest D polymorphism as a risk factor for hypertension in men. Other components in RAS, such as renin, angiotensinogen II type I receptor, or kallikrein have also been studied, but the available information is still incomplete. Genetic investigations of mendelian hypertension has identified the genetic mechanisms for glucocorticoid remediable aldosteronism, apparent mineral corticoid excess, and Liddle's syndrome as chimeric gene duplications of CYP11B1 (aldosterone synthase gene) and CYP11B2 (11beta-hydroxylase gene), mutations in the gene of 11beta-hydroxysteroid dehydrogenase type 2 that catalyzes the conversion of cortisol to cortisone, and mutations in beta or gamma subunit of epithelial sodium channel (ENaC), respectively. Subsequently, genetic variants of CYP11B2 and beta or gamma subunit of ENaC have been found, suggesting the -344C polymorphism of CYP11B2, 594S variant of betaENaC, and two rare variants of gammaENaC as risk factors for EHT. In spite of the extensive research, haplotypes in individual populations remain to be elucidcated in most candidate genes. Even casual conclusions of possible linkage with EHT need to be further examined with better determinations of phenotypes, such as ambulatory and home blood pressure monitoring or identification of onset of hypertension in cohort studies.
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PMID:Genetic determination of human essential hypertension. 1112 65

Blood pressure is determined by the product of cardiac output, intravascular volume, and peripheral resistance. Because hormones are involved in blood pressure regulation and affect these parameters, hypertension is a prominent feature of certain adrenal enzymatic abnormalities. In this report, two steroid-dependent forms of genetic low-renin hypertension are examined: 11beta-hydroxylase deficiency and apparent mineralocorticoid excess. 11beta-Hydroxylation is an enzymatic function necessary for the biosynthesis of cortisol by the zona fasciculata (ZF) of the adrenal cortex. Defects in this step lead to the abnormally increased production by the ZF of the steroid 11-deoxycorticosterone (DOC), a moderately potent mineralocorticoid, which causes sodium retention and volume expansion that result in hypertension. Further, the excess production of adrenal androgens leads to virilization, prenatally in the genetic female, and postnatally in both sexes. The disorder of 11beta-hydroxylase deficiency is due to an autosomal recessive defect of the enzyme protein-encoding gene CYP11B1. Numerous mutations in CYP11B1 causing 11beta-hydroxylase deficiency have been characterized. Apparent mineralocorticoid excess is a potentially fatal genetic disorder causing severe juvenile hypertension, pre- and postnatal growth failure, and low to undetectable levels of potassium, renin, and aldosterone. It is caused by autosomal recessive mutations in the HSD11B2 gene, which result in a deficiency of 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2).
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PMID:Hormonal hypertension in children: 11beta-hydroxylase deficiency and apparent mineralocorticoid excess. 1115 48

Mutations in the HSD11B2 gene encoding the kidney (11-HSD2) isozyme of 11beta-hydroxysteroid dehydrogenase cause the syndrome of apparent mineralocorticoid excess, a form of salt-sensitive hypertension. Enzymatic activities of mutant enzymes measured in cultured cells are correlated with several parameters of clinical severity including urinary steroid product:precursor ratios, age at diagnosis, birth weight and potassium levels, but not with blood pressure. In normals or in subjects with essential hypertension, sensitivity of blood pressure to salt loading is correlated with activity of renal 11-HSD2, as measured by an increase in the ratio of urinary free cortisol/urinary free cortisone (UFF/UFE), and also correlated with length of a CA repeat polymorphism in the first intron of HSD11B2. A functional explanation for these associations remains to be elucidated.
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PMID:Genotype-phenotype correlations of mutations and polymorphisms in HSD11B2, the gene encoding the kidney isozyme of 11beta-hydroxysteroid dehydrogenase. 1119 53

-In pregnancy, invading trophoblasts represent the inner vascular border of maternal spiral arteries and are exposed to elevated shear stress (ss) in hypertensive disorders. Intracellular cortisol availability is regulated by 11ss-hydroxysteroid dehydrogenases (11ss-HSDs), thus determining body fluid volume and vascular responses. The impact of ss on 11ss-HSD2 activity was studied in the human JEG-3 cell line, a model for trophoblasts. JEG-3 cells do not express 11ss-HSD1; however, 11ss-HSD2 message and activity are measured via cortisol/cortisone conversion in cell lysates, and both are reduced by ss. The reduction in 11ss-HSD2 activity via ss is dose dependent and completely reversible after the discontinuation of ss. cAMP-dependent protein kinase A activation increased the 11ss-HSD2 activity yet did not prevent the ss response. The ss response was completely protein kinase C independent. The mitogen-activated protein kinase kinase inhibitor PD-098059 enhanced 11ss-HSD2 activity in static conditions yet only ameliorated the ss effect. Cytochalasin D disrupts focal adhesion (FA)-cytoskeleton interactions and abolished the ss-induced tyrosine phosphorylation of FA kinase dose-dependently, thus maintaining 11ss-HSD2 activity. The 11ss-HSD2 activity was only partially restored by the tyrosine kinase inhibitor genistein; however, herbimycin A almost completely abolished the ss effect on 11ss-HSD2 activity. In conclusion, JEG-3 cells express 11ss-HSD2, which is downregulated by ss. Regulatory mechanisms involve transcriptional control and require intact FA-cytoskeleton signaling and phosphorylation of FA kinase. Thus, ss adds to an enhanced intracellular availability of cortisol, which may ultimately support a vasoconstrictive vascular response.
Hypertension 2001 Jan
PMID:Fluid Shear Stress Reduces 11ss-Hydroxysteroid Dehydrogenase Type 2. 1120 72

11beta-Hydroxysteroid dehydrogenases (11beta-HSD) interconvert cortisol, the physiological glucocorticoid, and its inactive metabolite cortisone in humans. There are two isoforms. The type 1 isoform (11beta-HSD1) catalyzes both 11beta-dehydrogenation (cortisol to cortisone) and the reverse oxoreduction (cortisone to cortisol), but the type 2 isoform (11beta-HSD2) catalyzes only 11beta-dehydrogenation. The diminished dehydrogenase activity has been demonstrated in resistance vessels of genetically hypertensive rats. However, the isoform(s) that plays a significant role in conferring the dehydrogenase activity on vasculature has not been determined. We investigated 11beta-HSD activities in human vascular smooth muscle cells by manipulating 11beta-HSD expressions with antisense oligonucleotides. The results showed that 11beta-HSD2 dominates functioning in the dehydrogenase mode in these cells. This indicates that impairment of 11beta-HSD2 activity in vascular wall may be related to the pathogenesis of hypertension.
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PMID:11beta-hydroxysteroid dehydrogenase activity in human aortic smooth muscle cells. 1121 28

The enzyme 11beta-hydroxysteroid dehydrogenase (11beta-HSD2) provides mineralocorticoid receptor specificity for aldosterone by metabolizing glucocorticoids to their receptor-inactive 11-dehydro derivatives. The present study investigated the effects of the aldosterone receptor antagonists spironolactone and eplerenone on endothelial function in liquorice-induced hypertension. Glycyrrhizic acid (GA), a recognized inhibitor of 11beta-HSD2, was supplemented to the drinking water (3 g/L) of Wistar-Kyoto rats over a period of 21 days. From days 8 to 21, spironolactone (5.8+/-0.6 mg. kg(-1). d(-1)), eplerenone (182+/-13 mg. kg(-1). d(-1)), or placebo was added to the chow (n=7 animals per group). Endothelium-dependent or -independent vascular function was assessed as the relaxation of preconstricted aortic rings to acetylcholine or sodium nitroprusside, respectively. In addition, aortic endothelial nitric oxide synthase (eNOS) protein content, nitrate tissue levels, and endothelin-1 (ET-1) protein levels were determined. GA increased systolic blood pressure from 142+/-8 to 185+/-9 mm Hg (P<0.01). In the GA group, endothelium-dependent relaxation was impaired compared with that in controls (73+/-6% versus 99+/-5%), whereas endothelium-independent relaxation remained unchanged. In the aortas of 11beta-HSD2-deficient rats, eNOS protein content and nitrate tissue levels decreased (1114+/-128 versus 518+/-77 microgram/g protein, P<0.05). In contrast, aortic ET-1 protein levels were enhanced by GA (308+/-38 versus 497+/-47 pg/mg tissue, P<0.05). Both spironolactone and eplerenone normalized blood pressure in animals on GA (142+/-9 and 143+/-9 mm Hg, respectively, versus 189+/-8 mm Hg in the placebo group; P<0.01), restored endothelium-dependent relaxation (96+/-3% and 97+/-3%, respectively, P<0.01 versus placebo), blunted the decrease in vascular eNOS protein content and nitrate tissue levels, and normalized vascular ET-1 levels. This is the first study to demonstrate that aldosterone receptor antagonism normalizes blood pressure, prevents upregulation of vascular ET-1, restores NO-mediated endothelial dysfunction, and thus, may advance as a novel and specific therapeutic approach in 11beta-HSD2-deficient hypertension.
Hypertension 2001 Feb
PMID:Aldosterone receptor antagonism normalizes vascular function in liquorice-induced hypertension. 1123 Mar 76

Renal 11beta-hydroxysteroid dehydrogenase type 2 (11betaHSD2) is an enzyme responsible for the peripheral inactivation of cortisol to cortisone in mineralocorticoid target tissues. Mutations in the gene encoding 11betaHSD2 cause the syndrome of apparent mineralocorticoid excess (AME), an autosomal recessive form of inherited hypertension, in which cortisol acts as a potent mineralocorticoid. The mutations reported to date have been confined to exons 3-5. Here, we describe two siblings, 1 and 2 yr old, who were diagnosed with hypokalemic hypertension and low plasma aldosterone and renin levels, indicating mineralocorticoid hypertension. Analysis of urinary steroid metabolites showed a markedly impaired metabolism of cortisol, with (tetrahydrocortisol + 5alpha-tetrahydrocortisol)/tetrahydrocortisone ratios of 40-60, and nearly absent urinary free cortisone. Although phenotypically normal, the heterozygous parents showed a disturbed cortisol metabolism. Genetic analysis of the HSD11B2 gene from the AME patients revealed the homozygous deletion of six nucleotides in exon 2 with the resultant loss of amino acids Leu(114) and Glu(115), representing the first alteration found in the cofactor-binding domain. The deletion mutant, expressed in HEK-293 cells, showed an approximately 20-fold lower maximum velocity but increased apparent affinity for cortisol and corticosterone. In contrast, two additionally constructed substitutions, Glu(115) to Gln or Lys, showed increased maximal velocity and apparent affinity for 11beta-hydroxyglucocorticoids. Functional analysis of wild-type and mutant proteins indicated that a disturbed conformation of the cofactor-binding domain, but not the missing negative charge of Glu(115), led to the observed decreased activity of the deletion mutant. Considered together, these findings provide evidence for a role of Glu(115) in determining cofactor-binding specificity of 11betaHSD2 and emphasize the importance of structure-function analysis to elucidate the molecular mechanism of AME.
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PMID:A mutation in the cofactor-binding domain of 11beta-hydroxysteroid dehydrogenase type 2 associated with mineralocorticoid hypertension. 1123 16

Apparent mineralocorticoid excess (AME) is a potentially fatal genetic disorder causing severe juvenile hypertension, pre- and postnatal growth failure, hypokalemia and low to undetectable levels of renin and aldosterone. It is caused by autosomal recessive mutations in the HSD11B2 gene, which result in a deficiency of 11 beta-hydroxysteroid dehydrogenase type 2 (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. In 1998, a mild form of this disease was reported, which might represent an important cause of low-renin hypertension. Early and vigilant treatment might prevent or improve the morbidity and mortality of end-organ damage.
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PMID:Apparent mineralocorticoid excess. 1130 34

The regulation of renal 11beta-hydroxysteroid dehydrogenase type 2 (11betaHSD2) gene expression is poorly understood. Inhibition of expression can result in hypertension. An example of this is in ectopic adrenocorticotropin (ACTH) syndrome (EAS). Inhibition of 11betaHSD2 activity is suggested by the observed increased ratio of cortisol to cortisone in both plasma and urine. To investigate whether ACTH or ACTH-dependent steroids can modulate renal 11betaHSD2 gene expression we analysed renal 11betaHSD2 mRNA levels after treatment with ACTH of 1 H and 24 H and demonstrated no change in the levels of gene expression. We have demonstrated in this study that the expression of 11betaHSD2 in the kidney is unaltered by ACTH. The reduced inactivation of cortisol by 11betaHSD2 observed in EAS is likely to be in part due to end product inhibition or substrate overload of the enzyme by endogenous substrates (cortisol, corticosterone, etc) rather than inhibition of 11betaHSD2 at the transcriptional level by either ACTH or ACTH regulated steroids.
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PMID:Increased ACTH levels do not alter renal 11beta-hydroxysteroid dehydrogenase type 2 gene expression in the sheep. 1140 98


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