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)

Data related to genetics of congenital adrenal hyperplasia with emphasis on CYP21 gene defects are briefly outlined. Mutations of the StAR gene lead to impaired translocation of cholesterol from the outer mitochondrial membrane to the inner mitochondria, a rate limiting step in steroidogenesis in the adrenals and the gonads. The clinical picture is characterized by adrenal and gonadal insufficiency and sex reversal in XY individuals. Molecular defects of the CYP17 gene encoding 17alpha-hydroxylase can cause hypertension, impaired sexual maturation and impaired sexual differentiation in XY individuals. Molecular defects of the CYP11B1 gene lead to 11-hydroxylase deficiency, which is clinically expressed with virilization of the external genitalia of the female and precocious puberty in the male, as well as hypertension in both sexes. The HSD3beta1 and HSD3beta2 genes encode two isoenzymes (3betaHSDI and 3betaHSDII). The clinical picture results from either absence or diminished activity of type II 3betaHSD, resulting from mutations of the HSD3beta2 gene. The most frequent form of CAH (90% of all patients) is due to deletions, conversions or point mutations of the CYP21 gene, which encodes the enzyme 21-hydroxylase. There is a wide range of clinical expression primarily explained by the type of the molecular defect. The ratio of genotype to phenotype concordance varies in the different forms of the disease, the highest one being encountered in the non-classical form. Heterozygosity of CYP21 mutations may be expressed as premature pubarche.
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PMID:Genetic aspects of congenital adrenal hyperplasia. 1196 27

There is growing evidence to the effect that steroid hormones are associated with a complex phenotype of metabolic abnormalities usually referred to as the metabolic syndrome. The 3 beta-hydroxysteroid dehydrogenases/Delta(4,5)-isomerase (3 beta-HSD) is crucial to the biosynthesis of hormonal steroids, including aldosterone, cortisol, and testosterone. The objective of the present study was to examine the potential impact of a T-->C substitution at codon Leu(338) of the type I (HSD3B1) 3 beta-HSD gene on obesity, circulating hormones, and estimates of insulin, glucose, and lipid metabolism as well as blood pressure in 284 unrelated Swedish men born in 1944. The subjects were genotyped by using PCR amplification of exon 4 of the HSD3B1 gene followed by digestion with the restriction enzyme BglII. The frequency of allele T was 0.44 and that of allele C 0.56. Homozygotes for the C allele (n=75) had significantly (P<0.05) higher mean systolic and diastolic blood pressures compared to both heterozygotes (n=143) and homozygotes for the T allele (n=45). In addition, the C allele was significantly (P=0.018) more frequent among subjects with grade 1 hypertension (>140/90 mm Hg) compared to normotensive (<130/85 mm Hg) subjects. These results were all adjusted for the potential confounding effect of body mass index (BMI) and waist-to-hip ratio (WHR). Other measurements such as BMI, WHR, abdominal sagittal diameter, salivary cortisol, total testosterone, serum leptin, fasting insulin and glucose, and serum lipids were not different across the HSD3B1 genotype groups. In conclusion, a T-->C polymorphism at codon Leu(338) of exon 4 of the HSD3B1 gene is associated with elevated systolic and diastolic blood pressures. The pathogenic mechanism underlying this association is, however, uncertain from the present data and further studies are warranted.
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PMID:Polymorphism in exon 4 of the human 3 beta-hydroxysteroid dehydrogenase type I gene (HSD3B1) and blood pressure. 1205 49

11 beta-Hydroxysteroid dehydrogenase type 2 (11 beta-HSD2) plays a crucial role in converting hormonally active cortisol to inactive cortisone, thereby conferring specificity on the mineralocorticoid receptor. Mutations in the gene encoding 11 beta-HSD2 (HSD11B2) account for an inherited form of hypertension, the syndrome of apparent mineralocorticoid excess, in which cortisol induces hypertension and hypokalemia. A similar clinical picture to apparent mineralocorticoid excess occurs after the ingestion of licorice and carbenoxolone, which are competitive inhibitors of 11 beta-HSD2. Reduced 11 beta-HSD2 activity may explain the increased sodium retention in preeclampsia, renal disease, and liver cirrhosis. Substrate saturation of 11 beta-HSD2 occurs in Cushing's syndrome and explains the mineralocorticoid excess state that characterizes ectopic ACTH syndrome. Polymorphic variability in the HSD11B2 gene in part determines salt sensitivity, a forerunner for adult onset hypertension. Furthermore, reduced placental 11 beta-HSD2 expression might underpin the Barker hypothesis, the epidemiological link between reduced birth weight and adult hypertension. At a prereceptor level, 11 beta-HSD2 plays a key role in normal physiology in the corticosteroid regulation of sodium homeostasis and pathophysiology of hypertension.
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PMID:Hypertension and the cortisol-cortisone shuttle. 1278 32

Progesterone (P) is a potent antagonist of the human mineralocorticoid receptor (MR) in vitro. We have previously demonstrated effective downstream metabolism of P in the kidney. This mechanism potentially protects the MR from P action. Here, we have investigated the expression and functional activity of steroidogenic enzymes in human kidney. RT-PCR analysis demonstrated the expression of 5 alpha-reductase type 1, 5 beta-reductase, aldo-keto-reductase (AKR) 1C1, AKR1C2, AKR1C3, 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) type 2, and 17 alpha-hydroxylase/17,20-lyase (P450c17). The presence of 3 beta-HSD type 2 and P450c17 indicated that conversion of pregnenolone to dehydroepiandrosterone (DHEA) and to androstenedione may take place effectively in kidney. To investigate this further, we incubated kidney subcellular fractions with radiolabeled pregnenolone. This resulted in efficient formation of DHEA from pregnenolone, indicating both 17 alpha-hydroxylase and 17,20-lyase activities exerted by P450c17. Radiolabeled DHEA was converted via androstenedione, androstenediol, and testosterone, indicating both 3 beta-HSD type 2 activity and 17 beta-HSD activity. In addition, the conversion of testosterone to 5 alpha-dihydrotestosterone was detectable, indicating 5 alpha-reductase activity. In conclusion, we verified the expression and functional activity of several enzymes involved in downstream metabolism of P and androgen synthesis in human kidney. These findings may be critical to the understanding of water balance during the menstrual cycle and pregnancy and of sex differences in hypertension.
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PMID:The human kidney is a progesterone-metabolizing and androgen-producing organ. 1278 91

We report a rare case of virilizing adrenocortical adenoma complicated with Cushing's syndrome, thyroid papillary carcinoma and hypergastrinemia. A 45-year-old woman had a history of amenorrhea for 10 years, hypertension for 8 years, and diabetes mellitus for 3 years. Physical examination showed a masculinized woman with severe hirsutism, male-like baldness, deep voice, acne in the precordia, and clitorism. Plasma testosterone, DHEA-S and urinary 17-KS were high, and plasma cortisol level was it at the upper limit of the normal range, but it did not show a diurnal rhythm nor was suppressed by 2 and 8 mg of dexamethasone. Abdominal CT scan showed a left adrenal tumor (4.5 cm in size). Adrenal scintigram revealed uptake of the tracer on the left side, and plasma cortisol concentration was high in a blood sample from the left adrenal vein. Left adrenalectomy was performed. Histopathological features of resected adrenal tumor were consistent with those of adrenocortical adenoma, consisting of tumor cells with eosinophilic compact cytoplasm. Immunohistochemical staining for steroidogenic enzymes showed reactivity for P450sec, 3 beta-HSD, P450c17, P450c21 and P450c11. Plasma testosterone and cortisol levels decreased to the normal range postoperatively. The patient was also found to have a papillary thyroid carcinoma and hypergastrinemia. Our patient is a rare case of virilizing adrenocortical adenoma associated with Cushing's syndrome, thyroid papillary carcinoma, and hypergastrinemia.
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PMID:Virilizing adrenocortical adenoma with Cushing's syndrome, thyroid papillary carcinoma and hypergastrinemia in a middle-aged woman. 1280 38

The Systemic Lupus International Collaborating Clinics/American College of Rheumatology (ACR) Damage Index (SDI) is an accepted instrument to ascertain damage. It has been shown to vary among different SLE populations. The aim of this study was to assess SDI score, pattern and factors related to damage in Brazilian SLE outpatients. The SDI was obtained in 105 patients with a median age of 41 (5-95%, 19-61.7) years and a median SLE duration of 127 (17.6-345.9) months. Patients had a median SDI of 2 (0-8) and 81.9% had some damage (SDI > 0). Damage was associated with a higher number of ACR criteria for SLE in multivariate analysis (OR = 2.32, 95%CI = 1.23-4.37, P = 0.009). Antiphospholipid syndrome (APS) (OR = 9.82, 95%CI = 2.74-35.23, P < 0.001), methylprednisolone pulses (OR = 3.91, 95%CI = 1.19-12.81, P = 0.024), age (OR = 1.70, 95%CI = 1.02-1.13, P = 0.011) and prednisone use duration (OR = 1.01, 95%CI = 1.002-1.02, P = 0.020) were related to severe damage (SDI > or = 4). Hypertension was associated with renal, cardiac and atherosclerotic damage, as cyclophosphamide pulses were with premature menopause. In conclusion, damage was very frequent in Brazilian SLE patients, mainly due to skin involvement, compared to other SLE populations. The presence of APS was the major independent contributor to the development of severe damage. Arterial hypertension was identified as a common risk factor for renal, cardiac and atherosclerotic damage.
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PMID:Rate, pattern and factors related to damage in Brazilian systemic lupus erythematosus patients. 1459 30

11 beta-Hydroxysteroid dehydrogenase type 1 (11HSD1) catalyses the in vivo conversion of inactive to active glucocorticoids. It is a widespread, highly regulated enzyme which amplifies the ligand available for intracellular glucocorticoid receptors. Excessive glucocorticoid exposure causes central obesity, hypertension, dyslipidaemia and insulin resistance, as seen with elevated plasma cortisol in Cushing's syndrome. Transgenic mice over-expressing 11HSD1 in their white adipose tissue are obese, hypertensive, dyslipidaemic and insulin resistant. Further, 11HSD1 knockout mice are protected from these metabolic abnormalities. In human idiopathic obesity, circulating cortisol levels are not elevated but 11HSD1 mRNA and activity is increased in subcutaneous adipose. The impact of increased adipose 11HSD1 on pathways leading to metabolic complications remains unclear in humans. Pharmacological inhibition of 11HSD1 has been achieved in liver with carbenoxolone, which enhances hepatic insulin sensitivity. Newer selective 11HSD1 inhibitors are in development, which may achieve reduced cortisol action in adipose tissue and confer therapeutic benefit in obese patients.
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PMID:11 beta-hydroxysteroid dehydrogenase type 1 in obesity and the metabolic syndrome. 1502 74

11beta-Hydroxysteroid dehydrogenase type 2 (11beta-HSD2) plays a crucial role in converting hormonally active cortisol to inactive cortisone, thereby conferring specificity upon the mineralocorticoid receptor (MR). Mutations in the gene encoding 11beta-HSD2 (HSD11B2) account for an inherited form of hypertension, the syndrome of "Apparent Mineralocorticoid Excess" (AME) where cortisol induces hypertension and hypokalaemia. We report five different mutations in the HSD11B2 gene in four families from Oman with a total of 9 affected children suffering from AME. Sequence data demonstrate the previously described L114Delta6nt mutation in exon 2 and new mutations in exon 3 (A221V), exon 5 (V322ins9nt) and for the first time in exon 1 (R74G and P75Delta1nt) of the HSD11B2 gene. These additional mutations provide further insight into AME and the function of the 11beta-HSD2 enzyme. The prevalence of monogenic forms of hypertension such as AME remains uncertain. However, our data suggests AME may be a relevant cause of hypertension in certain ethnic groups, such as the Oman population.
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PMID:Molecular basis for the apparent mineralocorticoid excess syndrome in the Oman population. 1513 13

11beta-Hydroxysteroid dehydrogenase (11beta-HSD) enzymes catalyze the conversion of biologically inactive 11-ketosteroids into their active 11beta-hydroxy derivatives and vice versa. Inhibition of 11beta-HSD1 has considerable therapeutic potential for glucocorticoid-associated diseases including obesity, diabetes, wound healing, and muscle atrophy. Because inhibition of related enzymes such as 11beta-HSD2 and 17beta-HSDs causes sodium retention and hypertension or interferes with sex steroid hormone metabolism, respectively, highly selective 11beta-HSD1 inhibitors are required for successful therapy. Here, we employed the software package Catalyst to develop ligand-based multifeature pharmacophore models for 11beta-HSD1 inhibitors. Virtual screening experiments and subsequent in vitro evaluation of promising hits revealed several selective inhibitors. Efficient inhibition of recombinant human 11beta-HSD1 in intact transfected cells as well as endogenous enzyme in mouse 3T3-L1 adipocytes and C2C12 myotubes was demonstrated for compound 27, which was able to block subsequent cortisol-dependent activation of glucocorticoid receptors with only minor direct effects on the receptor itself. Our results suggest that inhibitor-based pharmacophore models for 11beta-HSD1 in combination with suitable cell-based activity assays, including such for related enzymes, can be used for the identification of selective and potent inhibitors.
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PMID:The discovery of new 11beta-hydroxysteroid dehydrogenase type 1 inhibitors by common feature pharmacophore modeling and virtual screening. 1675 88

11beta-Hydroxysteroid dehydrogenase activity in the kidneys of NISAG rats (rat strain with hereditary stress-induced arterial hypertension) was 1.5-fold higher than in WAG rats. An inverse relationship was observed in the liver of these animals. After stress exposure 11beta-hydroxysteroid dehydrogenase activity remained unchanged in the kidneys of NISAG and WAG rats, but significantly increased in the liver of NISAG rats. Functional activity of 11beta-hydroxysteroid dehydrogenase probably reflects the hypertensive state of NISAG rats.
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PMID:Activity of 11beta-hydroxysteroid dehydrogenase in tissues of hypertensive NISAG rats. 1692 57


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