Disease relevance of HSD11B2

• These results indicate a role for DNA methylation in HSD11B2 gene repression and suggest an epigenetic mechanism affecting this gene causally linked with hypertension [1].
• Nonfunctioning adenomas and those causing preclinical and overt Cushing's syndrome may represent a continuum with clinical manifestations depending mainly on tumor size and HSD11B2 expression levels [2].
• 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 [3].
• 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 [4].
• CONCLUSIONS: Weak associations are reported between the HSD11B2 gene, type 1 diabetes mellitus and nephropathy [5].

Psychiatry related information on HSD11B2

• Comparison with previous enzymology studies suggest the changing pattern of 11 beta-HSD2 mRNA is likely to be translated into enzyme activity and have significant parallels in human development [6].
• Clinical and autopsy studies of 14 patients treated with amphotericin B methyl ester (AME) for focal, disseminated, and nervous system mycotic infections revealed a high incidence of progressive neurologic dysfunction (dementia, akinesia, mutism, hyperreflexia, and tremor) and diffuse white matter degeneration [7].

High impact information on HSD11B2

• The syndrome of AME is a rare form of juvenile hypertension in which 11-HSD is defective [8].
• CpG islands covering the promoter and exon 1 of HSD11B2 were found to be densely methylated in tissues and cell lines with low expression but not those with high expression of HSD11B2 [1].
• Methylation of HSD11B2 promoter-luciferase constructs decreased transcriptional activity [1].
• Herein NF1 was identified as a strong HSD11B2 stimulatory factor [1].
• The enzyme 11 beta-hydroxysteroid dehydrogenase type 2 (11 beta HSD2) is selectively expressed in aldosterone target tissues, where it confers aldosterone selectivity for the mineralocorticoid receptor by inactivating 11 beta-hydroxyglucocorticoids [1].

Chemical compound and disease context of HSD11B2

• Association studies between the HSD11B2 gene (encoding human 11beta-hydroxysteroid dehydrogenase type 2), type 1 diabetes mellitus and diabetic nephropathy [5].
• Thus, in patients with congenital deficiency of 11 beta-HSD (the syndrome of apparent mineralocorticoid excess, AME), cortisol and not aldosterone acts as a mineralocorticoid, resulting in hypertension and hypokalaemia with suppression of the renin-angiotensin-aldosterone axis [9].
• Here we show that administration of carbenoxolone, an inhibitor of placental 11 beta-HSD 2, to pregnant rats, leads to a significant reduction in average birth weight (20% fall) [10].
• Deficiency of the 11 beta-HSD2 isoform, as described in the syndrome of apparent mineralocorticoid excess and following liquorice (glycyrrhetinic acid) or carbenoxolone ingestion, results in hypertension in which cortisol acts as a potent mineralocorticoid [11].
• Administration of dexamethasone (which is poorly metabolized by placental 11 beta-HSD2) to pregnant rats resulted in decreased birth weight and the development of hypertension in the pups when adult [12].

Biological context of HSD11B2

• Using dimethyl sulfate in vivo footprinting via ligation-mediated PCR, we identified potentially important regions for HSD11B2 regulation in human cell lines: two GC-rich regions in the first exon (I and II) and two upstream elements (III and IV) [13].
• Genetic association of 11 beta-hydroxysteroid dehydrogenase type 2 (HSD11B2) flanking microsatellites with essential hypertension in blacks [14].
• In the present study, we describe the clinical and molecular genetic characterization of a patient with a new mutation in the HSD11B2 gene [15].
• Taken together, these findings suggest that activation of PPAR delta down-regulates HSD11B2 gene expression in human trophoblast cells, and that this effect is mediated primarily at the transcriptional level [16].
• This is the first study to definitively show that point mutations in the HSD11B2 gene abolish 11 beta HSD2 enzymatic activity in the syndrome of AME [17].

Anatomical context of HSD11B2

• These effects of carbenoxolone require intact maternal adrenal glands suggesting that inhibition of feto-placental 11 beta-HSD 2 is key [10].
• Western blot analysis showed a band at 41 kDa in endometrium and myometrium, confirming the presence of 11 beta HSD2 [18].
• There was no detectable mineralocorticoid receptor binding in endometrial cytosols prepared from patients with a range of 11 beta HSD2 activities [18].
• The intracellular localization of 11 beta HSD2 in kidney and colon epithelial cells was addressed using confocal laser microscopy [19].
• Widespread abundant 11 beta-HSD2 mRNA expression from E9.5-E12.5 changes dramatically at approximately E13 to a limited tissue-specific pattern (kidney, hindgut, testis/bile ducts, lung and a few brain regions (later seen in cerebellum, thalamus, roof of midbrain, neuroepithelial regions in pons and near the subicular hippocampus)) [6].

Associations of HSD11B2 with chemical compounds

• In 1995, it was shown that mutations in the gene (HSD11B2) encoding the 11beta-hydroxysteroid dehydrogenase type 2 enzyme (11beta-HSD2) cause AME [20].
• Molecular analysis of the HSD11B2 gene of this patient showed a homozygous C-->T transition in the second nucleotide of codon 227, resulting in a substitution of proline with leucine (P227L) [20].
• Approximately 5% conversion of cortisol to cortisone is predicted in subjects with mutations that completely inactivate HSD11B2, suggesting that a low level of enzymatic activity is mediated by another enzyme, possibly 11-HSD1 [21].
• This suggest that some essential hypertensives, with suppressed renin activity, may have an impairment in the cortisol inactivation catalyzed by the enzyme 11betaHSD2, whose low activity in LREH patients could be associated with the length of CA-repeat microsatellite in intron 1 of the HSD11B2 gene [22].
• Furthermore, cadmium diminished HSD11B2 promoter activity, indicative of repression of HSD11B2 gene transcription [23].

Physical interactions of HSD11B2

• Reduction of glucocorticoid receptor ligand binding by the 11-beta hydroxysteroid dehydrogenase type 2 inhibitor, Thiram [24].

Co-localisations of HSD11B2

• These results suggest that the 11 beta HSD2 enzyme colocalizes with the mineralocorticoid receptor in the distal nephron where it allows aldosterone to occupy its physiological receptor [25].

Regulatory relationships of HSD11B2

• Chenodeoxycholic acid and deoxycholic acid inhibit 11 beta-hydroxysteroid dehydrogenase type 2 and cause cortisol-induced transcriptional activation of the mineralocorticoid receptor [26].
• 11 beta HSD2 expression is markedly induced in ACTH-secreting pituitary tumors and, by converting F to E, may explain the resetting of glucocorticoid feedback control in Cushing's disease [27].
• The tissue-specific distribution of the 11 beta-HSD isoforms is in keeping with their differential roles, 11 beta-HSD1 regulating glucocorticoid hormone action and 11 beta-HSD2 mineralocorticoid hormone action [28].
• CONCLUSIONS: The increase in cortisol/cortisone ratio in urine but not in plasma, and the lack of effect on hepatic cortisol metabolites, suggests that GH inhibits both the conversion of cortisol to cortisone by renal 11 beta-HSD2 and the conversion of cortisone to cortisol by hepatic 11 beta-HSD1 [29].
• The AME-1 cell line expressed c-Met both at the mRNA and protein levels [30].

Other interactions of HSD11B2

• 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 [31].
• These data suggest that 11 beta HSD2 plays an important role in modulating mineralocorticoid and glucocorticoid receptor occupancy by glucocorticoids [32].
• Sequence alignment shows that 11 beta HSD2 shares 35% identity with 17 beta HSD2, but is only 14% identical with 11 beta HSD1 [32].
• Because approximately 40% of patients with essential hypertension demonstrate low renin, we suggest that such patients should undergo genetic analysis of the HSD11B2 gene [20].
• A microsatellite marker within the HSD11B2 gene associates with salt sensitivity and hypertension--phenotypes characterising diabetic nephropathy [5].

Analytical, diagnostic and therapeutic context of HSD11B2

• Parallel measurements of 11 beta HSD2 and nuclear propidium iodide fluorescence on sections scanned through an optical section of approximately 0.1 micron indicated significant 11 beta HSD2 immunofluorescence in the nucleus [19].
• Immunohistochemical studies on frozen sections of human kidney showed strong 11 beta HSD2 immunoreactivity in the cortical distal convoluted tubules and collecting ducts [25].
• Northern blot analysis of RNA isolated from JEG-3 cells after these treatments demonstrated a marked increase in a 1.9 kb 11 beta-HSD2 mRNA species in cells treated with forskolin for 24 h [33].
• Immunohistochemistry localized 11 beta-HSD1 to decidualized stromal cells and 11 beta-HSD2 to villous cytotrophoblast, syncytiotrophoblasts and trophoblast cells invading the placental bed and maternal vasculature [34].
• Urinary free cortisol and free cortisone were measured by radioimmunoassay as a measure of renal 11 beta-HSD-2 activity [35].

References