In mammalian tissues, at least two isozymes of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) catalyze the interconversion of hormonally active C11-hydroxylated corticosteroids (cortisol, corticosterone) and their inactive C11-keto metabolites (cortisone, 11-dehydrocorticosterone). The type 1 and type 2 11 beta-HSD isozymes share only 14% homology and are separate gene products with different physiological roles, regulation, and tissue distribution. 11 beta-HSD2 is a high affinity NAD-dependent dehydrogenase that protects the mineralocorticoid receptor from glucocorticoid excess; mutations in the HSD11B2 gene explain an inherited form of hypertension, the syndrome of apparent mineralocorticoid excess in which cortisol acts as a potent mineralocorticoid (Stewart and Krozowski, 1999).
NCBI Summary:
There are at least two isozymes of the corticosteroid 11-beta-dehydrogenase, a microsomal enzyme complex responsible for the interconversion of cortisol and cortisone. The type I isozyme has both 11-beta-dehydrogenase (cortisol to cortisone) and 11-oxoreductase (cortisone to cortisol) activities. The type II isozyme, encoded by this gene, has only 11-beta-dehydrogenase activity. In aldosterone-selective epithelial tissues such as the kidney, the type II isozyme catalyzes the glucocorticoid cortisol to the inactive metabolite cortisone, thus preventing illicit activation of the mineralocorticoid receptor. In tissues that do not express the mineralocorticoid receptor, such as the placenta and testis, it protects cells from the growth-inhibiting and/or pro-apoptotic effects of cortisol, particularly during embryonic development. Mutations in this gene cause the syndrome of apparent mineralocorticoid excess and hypertension. [provided by RefSeq, Feb 2010]
General function
Metabolism, Enzyme, Oxidoreductase
Comment
The enzyme 11 beta HSD catalyzes the interconversion of the biologically active cortisol and the biologically inactive cortisone. There are two distinct isozymes: 11 beta HSD type 2 is mainly expressed in kidney and is a unidirectional enzyme with only dehydrogenase activity. 11 beta HSD type 2 protects the mineralocorticoid receptor from being activated by cortisol. Thus, specificity of this receptor in vivo is enzyme and not receptor mediated. The syndrome of apparent mineralocorticoid excess is caused by a congenital deficiency of 11 beta HSD type 2 (Kerstens and Dullaart 1999.
Cellular localization
Cytoplasmic
Comment
Fluorescence microscopy demonstrated the localization of both 11beta-HSD1 and 11beta-HSD2 exclusively to the endoplasmic reticulum (ER) membrane. The N terminus of 11beta-HSD2 is lumenal, and the catalytic domain is facing the cytoplasm (Odermatt et al., 1999).
Glucocorticoid Metabolism in the Bovine Cumulus-Oocyte Complex matured in vitro. Tetsuka M et al. (2015) Glucocorticoid action in target organs is regulated by relative activities of 11β-HSD type1 (HSD11B1) that mainly converts cortisone to active cortisol, and type2 (HSD11B2) that inactivates cortisol to cortisone. HSD11Bs have been shown to be expressed in the ovary in various species. However, little is known about the expression and activity of HSD11Bs in the bovine cumulus-oocyte complex (COC). In the present study, we investigated expressions and activities of HSD11Bs in in vitro-matured (IVM) bovine COCs. Bovine COCs were matured in M199 supplemented with/without FSH and FCS. The expression of HSD11Bs was measured by using quantitative RT-PCR in denuded oocytes (DO) and cumulus cells (CC). Reductive and oxidative activities of HSD11Bs were determined by radiometric conversion assay using labeled cortisol, cortisone or dexamethasone in intact COC, DO or CC in the presence/absence of 11-keto-progesterone (11kP), a selective inhibitor of HSD11B2. The presence of 11HSDs in the oocyte was examined by immunofluorescence microscopy. Oocyte exclusively expressed HSD11B2 and its expression and activity were largely unchanged during IVM. Cumulus cells, on the other hand, exclusively expressed HSD11B1 and its expression and activity were up regulated as IVM progressed. As the results, the net glucocorticoid metabolism shifted from inactivation to activation towards the end of IVM. These results indicate that the bovine COC is capable to modulate local glucocorticoid concentration and by doing so, may create environment that is favorable to ovulating oocyte for maturation, fertilization and subsequent development.//////////////////
Human ovarian granulosa cells have been shown to possess both dehydrogenase and reductase 11betaHSD activities. Non-luteinized granulosa cells express relatively high levels of 11betaHSD2 mRNA. Conversely, luteinizing granulosa cells abundantly express 11betaHSD1 mRNA but not 11betaHSD2. CL also expresses 11betaHSD2 to lesser extent. Neither 11betaHSD mRNA is detectable in ovarian stroma. These results indicate that mRNAs encoding both 1lbetaHSD isozymes are present in human granulosa cells and they are developmentally--but differentially--regulated during preovulatory follicular development. The existence of developmentally regulated 11betaHSD in human granulosa cells is important new evidence that glucocorticoids, acting directly on the ovary, serve physiologically significant roles in the regulation of folliculogenesis (Tetsuka et al., 1997) and Ricketts et al., 1998.
Changes in mouse granulosa cell gene expression during early luteinization. McRae RS et al. Changes in gene expression during granulosa cell luteinization have been measured using serial analysis of gene expression (SAGE). Immature normal mice were treated with pregnant mare serum gonadotropin (PMSG) or PMSG followed, 48 h later, by human chorionic gonadotropin (hCG). Granulosa cells were collected from preovulatory follicles after PMSG injection or PMSG/hCG injection and SAGE libraries generated from the isolated mRNA. The combined libraries contained 105,224 tags representing 40,248 unique transcripts. Overall, 715 transcripts showed a significant difference in abundance between the two libraries of which 216 were significantly down-regulated by hCG and 499 were significantly up-regulated. Among transcripts differentially regulated, there were clear and expected changes in genes involved in steroidogenesis as well as clusters of genes involved in modeling of the extracellular matrix, regulation of the cytoskeleton and intra and intercellular signaling. The SAGE libraries described here provide a base for functional investigation of the regulation of granulosa cell luteinization.
Follicle stages
Preovulatory, Corpus luteum
Comment
Immunohistochemical Demonstration of the Mineralocorticoid Receptor, 11{beta}-Hydroxysteroid Dehydrogenase 1 and 2, and Hexose-6-Phosphate Dehydrogenase in Rat Ovary. Gomez-Sanchez EP et al. An immunohistochemical (IHC) survey using several monoclonal antibodies against different portions of the rat mineralocorticoid receptor (MR) molecule demonstrated significant specific MR immunoreactivity in the ovary, prompting further study of the localization of MR and determinants of extrinsic MR ligand specificity, 11ss-hydroxysteroid dehydrogenase 1 and 2 (11ss-HSD), and hexose-6-phosphate dehydrogenase (H6PDH). MR expression (real-time RT-PCR and western blot) did not differ significantly in whole rat ovaries at early diestrus, late diestrus, estrus, and a few hours after ovulation. MR immunostaining was most intense in corporal lutea cells, light to moderate in oocytes and granulosa cells, and least intense in theca cells. Light immunoreactivity for 11ss-HSD 2 occurred in most cells with some mural granulosa cells of mature follicles staining more strongly. The distribution of immunoreactivity for 11ss-HSD 1 and H6PDH required to generate NADPH, the co-factor required for reductase activity of 11ss-HSD 1, was similar, with the most intense staining in the cytoplasm of corporal lutea and theca cells and light or no staining in the granulosa and oocytes. MR function in the ovary is yet unclear, but distinct patterns of distribution of the 11ss-HSD 2, 11ss-HSD1 and H6PDH suggest that the ligand for MR activation in different cells of the ovary may be differentially regulated.
Phenotypes
Mutations
1 mutations
Species: human
Mutation name: R374X - Apparent mineralcorticoid excess (AME)
type: naturally occurring fertility: fertile Comment: 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. Two isoforms of human 11 beta-HSD have been described, but it is the NAD-dependent type 2 isoform (11 beta-HSD2), first characterised in placental tissue, that is expressed in the mineralocorticoid target tissues, kidney and colon. We have analysed the 11 beta-HSD2 gene as a candidate gene in explaining the molecular basis of AME. The mutation in exon 5 of the 11 beta-HSD2 gene resulted in a premature stop site at codon 374 instead of a normal arginine (R374X), with the deletion of 32 aminoacids from the C-terminus of the 11 beta-HSD2 enzyme protein. Both parents, who are phenotypically normal, are heterozygote for the C1228T mutation in keeping with an autosomal recessive form of inheritance. NAD-dependent 11 beta-HSD activity was severely attenuated in the stillbirth placenta compared with control placental tissue, and no 11 beta-HSD immunostaining was observed in this placenta with antisera derived against a C-terminal 11 beta-HSD2 peptide sequence. AME is due to a mutation in the 11 beta-HSD2 gene, and is an example of human hypertension arising from a single gene defect (Stewart et al.1996).