Gene Structure and Chromosomal Localization of the Human HSD11K Gene Encoding the Kidney (Type 2) Isozyme of 11β-Hydroxysteroid Dehydrogenase

doi:10.1006/geno.1995.1231

Genomics

Volume 29, Issue 1, 1 September 1995, Pages 195-199

https://doi.org/10.1006/geno.1995.1231 Get rights and content

Abstract

11β-Hydroxysteroid dehydrogenase (11βHSD) converts glucocorticoids to inactive products and is thus thought to confer specificity for aldosterone on the type I mineralocorticoid receptor in the kidney. Recent studies indicate the presence of at least two isozymes of 11βHSD. In vitro, the NAD⁺-dependent kidney (type 2) isozyme catalyzes 11β-dehydrogenase but not reductase reactions, whereas the NADP⁺-dependent liver (type 1) isozyme catalyzes both reactions. We have now characterized the human gene encoding kidney 11βHSD (HSD11K). A bacteriophage P1 clone was isolated after screening a human genomic library by hybridization with sheep HSD11K cDNA. The gene consists of 5 exons spread over 6 kb. The nucleotide binding domain lies in the first and the second exon, and the catalytic domain in the fourth exon. The 5′ flanking sequences and first exon are GC-rich (80%), suggesting that the gene may he transcriptionally regulated by factors that recognize GC-rich sequences. Fluorescence in situ hybridization of metaphase chromosomes with a positive P1 clone localized the gene to chromosome 16q22. In contrast, the HSD11L (liver isozyme) gene is located on chromosome 1 and contains 6 exons; the coding sequences of these genes are only 21% identical. HSD11K is expressed at high levels in the placenta and kidney of midgestation human fetuses and at lower levels in lung and testes. Different transcriptional start sites are utilized in kidney and placenta. These data should be applicable to genetic analysis of the syndrome of apparent mineralocorticoid excess, which may represent a deficiency of 11βHSD.

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Glucocorticoid metabolism and activation
2018, Encyclopedia of Endocrine Diseases
Glucocorticoid metabolism prior to receptor binding represents an important regulatory step that governs their action. The expression and activity of many different enzymes involved in this process have been described, including the isozymes of 11β-hydroxysteroid dehydrogenase and the A-ring reductases (5α- and 5β-reductase). Mutations in the genes encoding these enzymes cause specific pathological phenotypes and dysregulation of their activity and expression has been implicated in the pathogenesis of common clinical conditions.
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2018, Encyclopedia of Endocrine Diseases
11 β-Hydroxysteroid dehydrogenase type 2 (11β-HSD2) normally converts active cortisol to inactive cortisone and protects mineralocorticoid receptor (MR) occupied by cortisol. The syndrome of apparent mineralocorticoid excess is caused by impairment of the enzyme 11β-HSD2 leading to excessive cortisol that is able to activate MR. The clinical syndrome is typically characterized by hypertension with hypokalemia, metabolic alkalosis, low renin activity, and low aldosterone level. The etiology is inherited in autosomal recessive form, mutations in 11β-HSD2 gene or acquired form by ingestion of competitive inhibitors of 11β-HSD2 such as liquorice. Uncontrolled hypertension and prolong hypokalemia are the leading causes of end organ damages and cardiovascular mortality.
Investigating interactions between early life stress and two single nucleotide polymorphisms in HSD11B2 on the risk of schizophrenia
2015, Psychoneuroendocrinology
To examine the risk of schizophrenia in a Danish population after exposure to early life stress, and whether this risk is modified by DNA sequence variation, specifically two single nucleotide polymorphisms (SNPs) (rs5479 and rs56303414) from the gene HSD11B2. This gene encodes the enzyme 11-β hydroxysteroid dehydrogenase type 2 which converts active cortisol into inactive cortisone.
A two-stage analysis involving (1) a population-based cohort study, and (2) a nested case-control study using genotype information. Stage 1 included 1,141,447 people; here, we calculated incidence rate ratios (IRR) for the risk of schizophrenia among children of mothers who experienced loss or serious illness of close relatives before, during, and after pregnancy. In stage 2, we genotyped rs5479 and rs56303414 among 1275 schizophrenia cases and 1367 controls, and investigated interactions between genotypes and early life stress on the risk of schizophrenia.
In stage 1, no increased risk of schizophrenia was found in offspring after exposure during pregnancy, but offspring exposed to early life stress at age 0–2 years had a significantly increased risk of schizophrenia (adjusted IRR 1.18, 95% confidence interval 1.07–1.31). For rs5479, the minor allele was nucleotide A, and the major allele was nucleotide C. No interaction was found between rs5479 and exposure during pregnancy. Individuals with the minor A allele of rs5479, however, had a significantly increased risk of schizophrenia after exposure to early life stress at age 3–9 years (adjusted IRR 2.06, 1.04–4.06). No interaction was found between rs56303414 and exposure in any of the time periods.
No association was found between exposure to early life stress during pregnancy and schizophrenia in the offspring investigated, whereas individuals exposed to early life stress within the first two years of life had an increased risk. No interaction was found between HSD11B2 and exposure during pregnancy, but individuals with the A allele of rs5479 had an increased risk of schizophrenia after exposure at age 3–9 years.
Brain mineralocorticoid receptors in cognition and cardiovascular homeostasis
2014, Steroids
Citation Excerpt :
The existence of other 11β-HSDs has been postulated [213–215] and an 11β-HSD3 has been described in porcine testes [216]. Cloning and characterization of 11β-HSD2 [217,218], clarified the confusion caused by experiments using tissue homogenates that tore the ER and juxtaposed enzymes and co-factors that normally reside in separate cellular compartments. 11β-HSD1 is bi-directional, but in the liver where it is most abundant it is responsible for the oxido-reduction of inactive cortisone and 11-dehydrocorticosterone, converting them to cortisol and corticosterone, thus increasing the intracellular availability of activating ligand for both the GR and MR, particularly in the liver, adipose tissue and hippocampus, where the MR is normally bound by glucocorticoids [219,220].
Mineralocorticoid receptors (MR) mediate diverse functions supporting osmotic and hemodynamic homeostasis, response to injury and inflammation, and neuronal changes required for learning and memory. Inappropriate MR activation in kidneys, heart, vessels, and brain hemodynamic control centers results in cardiovascular and renal pathology and hypertension. MR binds aldosterone, cortisol and corticosterone with similar affinity, while the glucocorticoid receptor (GR) has less affinity for cortisol and corticosterone. As glucocorticoids are more abundant than aldosterone, aldosterone activates MR in cells co-expressing enzymes with 11β-hydroxydehydrogenase activity to inactivate them. MR and GR co-expressed in the same cell interact at the molecular and functional level and these functions may be complementary or opposing depending on the cell type. Thus the balance between MR and GR expression and activation is crucial for normal function. Where 11β-hydroxydehydrogenase 2 (11β-HSD2) that inactivates cortisol and corticosterone in aldosterone target cells of the kidney and nucleus tractus solitarius (NTS) is not expressed, as in most neurons, MR are activated at basal glucocorticoid concentrations, GR at stress concentrations. An exception may be pre-autonomic neurons of the PVN which express MR and 11β-HSD1 in the absence of hexose-6-phosphate dehydrogenase required to generate the requisite cofactor for reductase activity, thus it acts as a dehydrogenase. MR antagonists, valuable adjuncts to the treatment of cardiovascular disease, also inhibit MR in the brain that are crucial for memory formation and exacerbate detrimental effects of excessive GR activation on cognition and mood. 11β-HSD1 inhibitors combat metabolic and cognitive diseases related to glucocorticoid excess, but may exacerbate MR action where 11β-HSD1 acts as a dehydrogenase, while non-selective 11β-HSD1&2 inhibitors cause injurious disruption of MR hemodynamic control. MR functions in the brain are multifaceted and optimal MR:GR activity is crucial. Therefore selectively targeting down-stream effectors of MR specific actions may be a better therapeutic goal.
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2014, Vitamins and Hormones
Citation Excerpt :
The human 11β-HSD2 is encoded by the HSD11B2 gene. Human HSD11B2 gene is located on chromosome 16q22 (Agarwal, Rogerson, Mune, & White, 1995b). The human HSD11B2 gene is about 6.2 kb in length (Agarwal, Rogerson, Mune, et al., 1995b).
Hydroxysteroid dehydrogenases (HSD) are a group of steroidogenic enzymes that are involved in the steroid biosynthesis and metabolism. Four classes of HSDs, namely, 3β-, 11β-, 17β-, and 20α-HSDs, are discussed. 3β-HSDs catalyze the conversion of pregnenolone, 17α-hydroxypregnenolone, and dehydroepiandrosterone to progesterone, 17α-hydroxyprogesterone, and androstenedione, respectively. 11β-HSDs catalyze the interconversion between active cortisol and inactive cortisone. 17β-HSDs catalyze the interconversion between 17β-hydroxyl steroids and 17-ketoandrogens and estrogens. 20α-HSDs catalyze the conversion of progesterone into 20α-hydroxyprogesterone. Many environmental pollutants directly inhibit one or more enzymes of these HSDs, thus interfering with endogenous active steroid hormone levels. These chemicals include industrial materials (perfluoroalkyl compounds, phthalates, bisphenol A, and benzophenone), pesticides/biocides (methoxychlor, organotins, 1,2-dibromo-3-chloropropane, and prochloraz), and plant constituents (genistein, gossypol, and licorice). This chapter reviews these inhibitors targeting on HSDs.

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Regular ArticleGene Structure and Chromosomal Localization of the Human HSD11K Gene Encoding the Kidney (Type 2) Isozyme of 11β-Hydroxysteroid Dehydrogenase

Abstract

Regular Article
Gene Structure and Chromosomal Localization of the Human HSD11K Gene Encoding the Kidney (Type 2) Isozyme of 11β-Hydroxysteroid Dehydrogenase