Association between a variant in the 11β-hydroxysteroid dehydrogenase type 2 gene and primary hypertension

Melander, Olle; Orho‐Melander, Marju; Bengtsson, Kristina; Lindblad, Ulf; Råstam, Lennart; Groop, Leif; Hulthén, U L

doi:10.1038/sj.jhh.1001116

Cited by 19 publications

(11 citation statements)

References 25 publications

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“…Among these polymorphisms is the presence of a CA-repeat microsatellite in intron 1 of the HSD11B2 gene, which has been correlated to high F/E ratios and a higher salt sensitivity [24,25]. In addition, other polymorphism markers had been described such as Thr156/Thr(C468A) in exon 2 (ex2) and Glu178/Glu(G534A) in exon 3 (ex3) present in a higher prevalence in hypertensive patients than in normotensives subjects [48,49]. However, this association was not correlated with salt sensitivity and only C468A correlated significantly with hypertension [49].…”

Section: Discussionmentioning

confidence: 96%

11β-hydroxysteroid dehydrogenase type-2 and type-1 (11β-HSD2 and 11β-HSD1) and 5β-reductase activities in the pathogenia of essential hypertension

Campino

Carvajal

Cornejo

et al. 2009

Endocr

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Cortisol availability is modulated by several enzymes: 11β-HSD2, which transforms cortisol (F) to cortisone (E) and 11β-HSD1 which predominantly converts inactive E to active F. Additionally, the A-ring reductases (5α- and 5β-reductase) inactivate cortisol (together with 3α-HSD) to tetrahydrometabolites: 5αTHF, 5βTHF, and THE. The aim was to assess 11β-HSD2, 11β-HSD1, and 5β-reductase activity in hypertensive patients. Free urinary F, E, THF, and THE were measured by HPLC-MS/MS in 102 essential hypertensive patients and 18 normotensive controls. 11β-HSD2 enzyme activity was estimated by the F/E ratio, the activity of 11β-HSD1 in compare to 11β-HSD2 was inferred by the (5αTHF + 5βTHF)/THE ratio and 5β-reductase activity assessed using the E/THE ratio. Activity was considered altered when respective ratios exceeded the maximum value observed in the normotensive controls. A 15.7% of patients presented high F/E ratio suggesting a deficit of 11β-HSD2 activity. Of the remaining 86 hypertensive patients, two possessed high (5αTHF + 5βTHF)/THE ratios and 12.8% had high E/THE ratios. We observed a high percentage of alterations in cortisol metabolism at pre-receptor level in hypertensive patients, previously misclassified as essential. 11β-HSD2 and 5β-reductase decreased activity and imbalance of 11β-HSDs should be considered in the future management of hypertensive patients.

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Section: Discussionmentioning

confidence: 96%

11β-hydroxysteroid dehydrogenase type-2 and type-1 (11β-HSD2 and 11β-HSD1) and 5β-reductase activities in the pathogenia of essential hypertension

Campino

Carvajal

Cornejo

et al. 2009

Endocr

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“…Such a mechanism is crucial for the kidney where cortisol is known to activate mineralocorticoid receptor and its inactivation by 11β-HSD2 is of great importance. Polymorphisms (Cys468Ala and Gly534Ala) in the gene that encodes 11βHSD2 were found associated with hypertension (Melander et al, 2000). Such a regulation of GCs can be named as the “pre-receptor” mechanism, i.e., prior to activation of the glucocorticoid GRα receptor and its translocation to the nucleus for either activation of repression of genes.…”

Section: Mechanisms That Control Levels Of Gcsmentioning

confidence: 99%

Glucocorticoid therapy and ocular hypertension

Dibas

Yorio

2016

European Journal of Pharmacology

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The projected number of people who will develop age-related macular degeneration in estimated at 2020 is 196 million and is expected to reach 288 million in 2040. Also, the number of people with Diabetic retinopathy will grow from 126.6 million in 2010 to 191.0 million by 2030. In addition, it is estimated that there are 2.3 million people suffering from uveitis worldwide. Because of the anti-inflammatory properties of glucocorticoids (GCs), they are often used topically and/or intravitreally to treat ocular inflammation conditions or edema associated with macular degeneration and diabetic retinopathy. Unfortunately, ocular GC therapy can lead to severe side effects. Serious and sometimes irreversible eye damage can occur as a result of the development of GC-induced ocular hypertension causing secondary open-angle glaucoma. According to the world health organization, glaucoma is the second leading cause of blindness in the world and it is estimated that 80 million will suffer from glaucoma by 2020. In the current review, mechanisms of GC-induced damage in ocular tissue, GC-resistance, and enhancing GC therapy will be discussed.

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“…Nevertheless, the allelic frequency of 11HSD2 polymorphism has not yet been fully described in the human population. 33,[150][151][152][153] All these considerations suggest the possibility of an involvement of the enzyme in some cases of essential hypertension.…”

Section: Congenital Deficiency Of 11hsd2 (Apparent Mineralocorticmentioning

confidence: 96%

“…11HSD activity may be only mildly impaired in the heterozygous state, and, in some cases, hypertension can be detected only in adulthood. 151 Moreover, there could be a specific polymorphism in 11HSD2, resulting in genetically based differences in the levels of its activity and finally in blood pressure levels. Nevertheless, the allelic frequency of 11HSD2 polymorphism has not yet been fully described in the human population.…”

Section: Congenital Deficiency Of 11hsd2 (Apparent Mineralocorticmentioning

confidence: 99%

“…These mutations are characterized by reduced gene expression and enzyme activity. [150][151][152][153][154][155] The measurement of cortisol/cortisone and of THF+ alloTHF/ THE ratios in urine is necessary for a correct diagnosis. An increase in these ratios is consistent with a reduction of 11HSD2 activity.…”

Section: Congenital Deficiency Of 11hsd2 (Apparent Mineralocorticmentioning

confidence: 99%

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Pseudohyperaldosteronism: Pathogenetic Mechanisms

Armanini

Calò

Semplicini

2003

Critical Reviews in Clinical Laboratory Sciences

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Pseudohyperaldosteronism is characterized by a clinical picture of hyperaldosteronism with suppression of plasma renin activity and aldosterone. Pseudohyperaldosteronism can be due to a direct mineralocorticoid effect, as with desoxycorticosterone, fluorohydrocortisone, fluoroprednisolone, estrogens, and the ingestion of high amounts of glycyrrhetinic acid. A block of 11-hydroxysteroid-dehydrogenase type 2 (11HSD2), the enzyme that converts cortisol into cortisone, at the level of epithelial target tissues of aldosterone, is involved in other cases. This mechanism is related either to a mutation of the gene, which encodes 11HSD2 (apparent mineralocorticoid excess syndrome and some cases of low renin hypertension) or to an acquired reduction of the activity of the enzyme due to glycyrrhetinic acid, carbenoxolone, and grapefruit juice. In other cases saturation of 11HSD2 may be involved as in severe Cushing's syndrome and chronic therapy with some corticosteroids. Recently, an activating mutation of the mineralocorticoid receptor gene has been described. Another genetic cause of pseudohyperaldosteronism is the syndrome of Liddle, which is due to a mutation of the gene encoding for beta and gamma subunits of the sodium channels.

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Association between a variant in the 11β-hydroxysteroid dehydrogenase type 2 gene and primary hypertension

Cited by 19 publications

References 25 publications

11β-hydroxysteroid dehydrogenase type-2 and type-1 (11β-HSD2 and 11β-HSD1) and 5β-reductase activities in the pathogenia of essential hypertension

11β-hydroxysteroid dehydrogenase type-2 and type-1 (11β-HSD2 and 11β-HSD1) and 5β-reductase activities in the pathogenia of essential hypertension

Glucocorticoid therapy and ocular hypertension

Pseudohyperaldosteronism: Pathogenetic Mechanisms

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