Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.1.1.3 (HSD)
3,464 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glucocorticoid access to renal corticosteroid receptors is regulated by 11beta-hydroxysteroid dehydrogenases (11beta-HSDs), converting 11beta-hydroxyglucocorticoids into inactive 11-ketones. This mechanism plays a key role in maintaining normal salt-water homeostasis and blood pressure. To study whether renal cortical proximal and distal tubular 11beta-HSDs are modulated, upon shifting the electrolyte status (and may thereby contribute to adjusting the salt-water homeostasis), rats were treated for 14 days with diets with low (0.058 w/w%), normal (0.58%, which is the KCl content of standard European laboratory rat food) or high (5.8%) potassium chloride content. In proximal tubules, dietary KCl had no effect regarding corticosterone 11beta-oxidation in intact cells as well as 11beta-HSD1 and 11beta-HSD2 protein (Western blotting) and mRNA levels (semi-quantitative RT-PCR). In distal tubules, the low KCl diet also had no effect. However, distal tubules of rats fed the high KCl diet showed increased corticosterone 11beta-oxidation rates (1.6-fold, P<0.01) and 11beta-HSD2 protein (4-fold, P<0.01), whereas 11beta-HSD1 protein was decreased (no longer detected, P<0.05). Distal tubular 11beta-HSD mRNA levels were not changed upon dietary treatment. Our results suggest that upon dietary KCl loading distal tubular mineralocorticoid receptor selectivity for aldosterone is increased because of enhanced corticosterone 11beta-oxidation. This may contribute to the fine-tuning of salt-water homeostasis by the kidney.
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PMID:High dietary potassium chloride intake augments rat renal mineralocorticoid receptor selectivity via 11beta-hydroxysteroid dehydrogenase. 1056 68

Glucocorticoids may underlie the association between prenatal stress, low birth weight and adult stress-associated disorders, e.g. hypertension and type 2 diabetes, increased hypothalamic-pituitary-adrenal (HPA) activity and affective dysfunction. Normally, 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) rapidly inactivates glucocorticoids in placenta and many foetal tissues, thus acting as a 'barrier' to maternal steroids. We investigated the effect of inhibiting foeto-placental 11beta-HSD in rats, using carbenoxolone (CBX), on subsequent HPA activity and regulation and stress-induced behaviour in adult offspring. Pregnant Wistar rats were injected with CBX (12.5 mg s.c.) or vehicle daily throughout pregnancy. CBX treatment reduced birth weight. Adult offspring of CBX-treated dams had persistently reduced body weight, increased basal corticosterone (CORT) levels, increased corticotropin-releasing hormone (CRH) and reduced glucocorticoid receptor (GR) mRNA in the hypothalamic paraventricular nucleus, though hippocampal GR and mineralocorticoid receptor (MR) mRNA expression were unaltered. In addition, these animals showed less grooming and rearing in an open field and reduced immobility in a forced swim test, and had increased GR mRNA expression in the basolateral (BLA), central (CEA) and medial (MEA) nuclei of the amygdala, with unaltered MR mRNA. These data suggest that disturbance of the foeto-placental enzymatic barrier to maternal glucocorticoids reduces birth and body weight, and produces permanent alterations of the HPA axis and anxiety-like behaviour in aversive situations. The behavioural and HPA effects may reflect GR gene programming in amygdala and hypothalamus, respectively. Foetal overexposure to endogenous glucocorticoids (prenatal stress or reduced activity of foeto-placental 11beta-HSD) may represent a common link between the prenatal environment, foetal growth and adult neuroendocrine and affective disorders.
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PMID:Inhibition of 11beta-hydroxysteroid dehydrogenase, the foeto-placental barrier to maternal glucocorticoids, permanently programs amygdala GR mRNA expression and anxiety-like behaviour in the offspring. 1076 36

The aim of the present study was to demonstrate rapid effects of aldosterone on the Na(+)-H(+) exchanger in strips of human vascular vessels and to determine whether 11beta-hydroxysteroid dehydrogenase enzyme (11beta-HSD) could play a protective role in this response, such as that described for the classic type I mineralocorticoid receptor (MR). The activity of 11beta-HSD isoforms 1 and 2 were measured in fetal and adult arteries. Both isoforms are present in adult and fetal vessels. However, a significant difference in the proportion of each isoform was found. Isoform 1 activity (in pmol x min(-1) x 100 mg(-1) protein) was 42+/-5 in fetal vessels and 29+/-2 in adult arteries, and isoform 2 activity was 78+/-7 in fetal and 12+/-2 in adult tissue. The nongenomic effect of aldosterone on Na(+)-H(+) exchanger activity was measured in strips of chorionic and radial uterine arteries loaded with the pH-sensitive dye 2',7'-bis(2-carboxyethyl)-5,6-carboxyfluorescein. Recordings of intracellular pH (pH(i)) were made by videofluorescence microscopy. Aldosterone (0.5 nmol/L) rapidly increased pH(i), with a half-maximal effect between 2 and 3 nmol/L in both fetal and adult vessels. Ethylisopropylamiloride, a specific inhibitor of the Na(+)-H(+) exchanger, inhibited this effect. The hormone-mediated increase in pH(i) was unaffected by spironolactone, a classic antagonist of MR, but was completely blocked by RU28318. Cortisol (up to 1 micromol/L) had no effect on pH(i), but when applied in the presence of carbenoxolone, a dramatic increase in Na(+)-H(+) exchanger activity was evident. The increments on pH(i) for each cortisol concentration were similar to those observed for aldosterone. These findings suggest that vascular 11beta-HSD plays an active role in maintaining the specificity of the rapid effects of aldosterone.
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PMID:Role of 11beta-hydroxysteroid dehydrogenase in nongenomic aldosterone effects in human arteries. 1081 71

Endocrine pathology is a well-recognised and important cause of human hypertension. Recent research has highlighted the role of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) in the development of certain forms of hypertension. This enzyme, which exists as two genetically unique isoforms, 11 beta-HSD1 and 11 beta-HSD2, is responsible for the interconversion of biologically active cortisol with its inactive 11-oxo derivative, cortisone. Congenital deficiency of 11 beta-HDS2 results in inappropriate activation of the renal mineralocorticoid receptor by cortisol, leading to hypertension, hypokalaemia and metabolic alkalosis. Several authors have postulated a link between changes in 11 beta-HSD activity and the development of certain forms of essential hypertension. The existence of endogenous inhibitors of the enzyme provides compelling evidence in favour of this hypothesis, but few have been able to demonstrate a clear link between inhibition of 11 beta-HSD2 activity and hypertension by this mechanism. Similarly, several authors have suggested a relationship between reduced placental 11 beta-HSD2 activity, low birth weight with high placental weight, and the development of hypertension in adulthood. However, no clear evidence to suggest a direct correlation between birth weight, placental weight and 11 beta-HSD2 activity has been demonstrated. While the role of 11 beta-HSD in the development of hypertension remains controversial, an understanding of the interplay of this enzyme with both mineralocorticoid and glucocorticoid receptors undoubtedly will yield data that will clarify this complex field.
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PMID:11 beta-Hydroxysteroid dehydrogenase: a link between the dysregulation of cortisol metabolism and hypertension. 1082 33

The hypothalamic-pituitary-adrenal axis is hyporesponsive to stress in late pregnancy, exemplified as reduced adrenocorticotropic hormone (ACTH) and corticosterone responses to restraint, but the mechanisms are unknown. We investigated forward drive and negative feedback upon the hypothalamic-pituitary-adrenal axis in pregnant rats. Corticotropin-releasing hormone (CRH) and vasopressin mRNA expression in the parvocellular paraventricular nucleus and mineralocorticoid and glucocorticoid receptor expression in the paraventricular nucleus and hippocampus were quantified with in situ hybridization. Because it can enhance the corticosterone negative feedback signal, 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) bioactivity in these brain regions and anterior pituitary was measured in vitro, and ACTH and corticosterone stress responses were measured after intracerebroventricular glycyrrhetinic acid, an 11beta-HSD inhibitor. Changes in corticosterone feedback on ACTH secretion were examined after pharmacological adrenalectomy by metyrapone and aminoglutethimide. Parvocellular paraventricular nucleus CRH mRNA content was reduced on day 21 and the CRH mRNA : vasopressin mRNA ratio was unaltered, indicating decreased production of both CRH and vasopressin. An increase in glucocorticoid receptor mRNA expression in the dentate gyrus (mineralocorticoid receptor mRNA expression was unaltered) and increased 11beta-HSD1 activity in the paraventricular nucleus and anterior pituitary suggest an increase in slow negative feedback mechanisms in pregnancy, but glycyrrhetinic acid did not modify the stress response. After metyrapone/aminoglutethimide treatment, corticosterone decreased ACTH secretion more slowly in pregnancy, indicating a decrease in rapid feedback sensitivity. Thus, reduced forward drive rather than increased effectiveness of glucocorticoid negative feedback may underlie stress hyporesponsiveness of the hypothalamic-pituitary-adrenal axis in pregnancy.
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PMID:Attenuation of hypothalamic-pituitary-adrenal axis stress responses in late pregnancy: changes in feedforward and feedback mechanisms. 1092 94

Renal 11beta-hydroxysteroid dehydrogenases (11beta-HSDs) are subject to modulation by various endogenous factors. 11beta-HSDs convert glucocorticoids into inactive 11-ketones and thereby determine tissue levels of active glucocorticoids and thus the extent of glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) activation. As such, modulation of the activity of renal 11beta-HSDs may contribute to the cascade of regulatory events involved in renal electrolyte water handling. We investigated whether renal 11beta-HSDs are modulated by elevated circulating angiotensin II. In rats infused for 2 wk with angiotensin II (250 ng/[kg x min] subcutaneously), plasma angiotensin II, aldosterone, and corticosterone were raised 5.1-, 10.7-, and 2.3-fold, respectively, compared with control rats. Angiotensin II infusion raised corticosterone 11beta-oxidation 1.46- and 1.35-fold in renal cortical proximal and distal tubules (enriched by Percoll centrifugation), respectively, but had no effect on 11beta-HSD1 and 11beta-HSD2 mRNA levels (semiquantitative reverse transcriptase polymerase chain reaction), except for distal tubular 11beta-HSD1 mRNA, which was decreased to 50%. In vitro treatment of freshly isolated tubules with angiotensin II for 45 min prior to assessment of 11beta-HSD activity showed no direct acute effects of angiotensin II on tubular corticosterone 11beta-oxidation. The enhanced renal tubular corticosterone 11beta-oxidation in vivo may partly protect renal GR and MR from elevated plasma corticosterone on angiotensin II infusion.
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PMID:Effect of angiotensin II on rat renal cortical 11beta-hydroxysteroid dehydrogenase. 1121 53

11beta-hydroxysteroid dehydrogenase (11beta-HSD) regulates local actions of corticosteroids at glucocorticoid and mineralocorticoid receptors. Corticosteroids are thought to play important roles in ocular function. However, mechanisms of intraocular corticosteroid action are still unclear. Therefore, in this study, we examined the immunohistochemical localization of 11beta-HSD type 1 (11beta-HSD1), 11beta-HSD type 2 (11beta-HSD2), mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) in human ocular tissues from patients (6 months to 78 years of age; n = 10) retrieved from surgical pathology files. Both 11beta-HSD2 and MR immunoreactivity was detected only in non-pigmented epithelium of the ciliary body, but was undetectable in cornea, lens, iris, retina, choroid and sclera, in all the cases examined. GR was detected in all cell types in the human eye. 11beta-HSD1 immunoreactivity was not detected in the human eye in this study. These results suggest that 11beta-HSD2 play an important role in human ocular mineralocorticoid action, such as the production of aqueous humor, in the ciliary body. The widespread expression of GR suggests that glucocorticoids may play an important role in the function and homeostasis of the human eye.
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PMID:Immunohistochemical distribution of 11beta-hydroxysteroid dehydrogenase in human eye. 1122 83

Two isoforms of the enzyme 11beta-hydroxysteroid dehydrogenase (11beta-HSD) interconvert the active glucocorticoid, cortisol, and inactive cortisone. 11beta-HSD1 is believed to act in vivo predominantly as an oxo-reductase using NADP(H) as a cofactor to generate cortisol. In contrast, 11beta-HSD2 acts exclusively as an NAD-dependent dehydrogenase inactivating cortisol to cortisone, thereby protecting the mineralocorticoid receptor from occupation by cortisol. In peripheral tissues, both enzymes serve to control the availability of cortisol to bind to the corticosteroid receptors. Defective expression of 11beta-HSD2 is implicated in patients with hypertension and intra-uterine growth retardation, while 11beta-HSD1 appears to be intricately involved in the conditions of apparent cortisone reductase deficiency, insulin resistance and visceral obesity. The ability of peripheral tissues to regulate corticosteroid concentrations through 11beta-HSD isozymes is established as an important mechanism in the pathogenesis of diverse human diseases. Modulation of enzyme activity may offer a novel therapeutic approach to treating human disease while circumventing the consequences of systemic glucocorticoid excess or deficiency.
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PMID:Cortisol metabolism and the role of 11beta-hydroxysteroid dehydrogenase. 1146 11

11beta-Hydroxysteroid dehydrogenase 2 (11beta-HSD 2) converts active cortisol to inactive cortisone and thus modifies the availability of glucocorticoids for the target tissue. An additional function is the protection of the aldosterone receptor in mineralocorticoid-sensitive tissues such as the kidney and the gut. The occurrence of 11beta-HSD 2 activity was investigated in several species. Data for the pig, however, so far are missing. The activity was determined by a radio-enzyme-assay based on the conversion of tritiated cortisol to cortisone under standardized incubation conditions in supernatants of homogenates prepared from tissues of four castrates. Tissues comprised several locations along the intestinal tract and in addition kidney, lung, muscle, heart, spleen and pancreas. Highest values of the enzyme activity were found in kidney and very low activities in lung tissue but no activity in muscle, spleen, heart and pancreas. In the gut, there was a continuous increase in enzyme activity from the duodenum (0.60 pmol x min(- 1) x mg protein(- 1)) towards the colon with maximum values in the colon transversum (23.32 pmol x min(- 1) x mg protein(- 1)). In the colon the activity was 10-fold higher than in jejunum and 3-fold higher compared to ileum. The activities did not differ significantly between the colon transversum and colon descendens.
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PMID:Activities of 11beta-hydroxysteroid dehydrogenase 2 in different regions of the intestinal tract of pigs. 1157 49

Loss-of-function mutations or inhibition of 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD-2) results in overstimulation of the mineralocorticoid receptor by cortisol and causes salt-sensitive hypertension. Traditionally, 11beta-HSD-2 activity has been assessed by measurement of the urinary cortisol metabolite ratio (tetrahydrocortisol [THF]+5alpha-THF)/tetrahydrocortisone (THE). Recently, the ratio of urinary free glucocorticoids, UFF/UFE, has been suggested to be a more reliable parameter, an aspect that has not been investigated systematically. Steroid metabolites were measured repeatedly by gas chromatography-mass spectrometry in 20 healthy subjects at baseline and after 1 week each of a 30- or 180-mmol/d of sodium diet or 500 mg/d of glycyrrhetinic acid. Intraindividual coefficients of variation from 3 random urine collections for (THF+5alpha-THF)/THE and UFF/UFE ratios were 11+/-9% and 25+/-14% (P<0.001). (THF+5alpha-THF)/THE was more sensitive than UFF/UFE for detection of glycyrrhetinic acid-induced increases higher than the upper 95% confidence interval of the coefficient of variation of the corresponding ratio. Low- or high-salt diet did not alter either ratio. Mean (THF+5alpha-THF)/THE but not UFF/UFE was higher in salt-sensitive than salt-resistant subjects. Absolute glycyrrhetinic acid-related increase in (THF+5alpha-THF)/THE but not UFF/UFE was higher in salt-sensitive than salt-resistant subjects and correlated with changes in mean BP. Intraindividual variability of (THF+5alpha-THF)/THE is lower than that of UFF/UFE. The UFF/UFE ratio does not appear to be more sensitive than (THF+5alpha-THF)/THE for detection of decreased 11beta-HSD-2 activity. The (THF+5alpha-THF)/THE ratio better discriminates between salt-sensitive and salt-resistant subjects. Together with BP responses to glycyrrhetinic acid, these findings support a pivotal role of 11beta-HSD-2 in salt sensitivity.
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PMID:In vivo 11beta-HSD-2 activity: variability, salt-sensitivity, and effect of licorice. 1175 13


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