Disease relevance of Hsd11b1

• Early inflammatory responses in experimental cardiac hypertrophy and fibrosis: effects of 11 beta-hydroxysteroid dehydrogenase inactivation [1].
• To examine the relationship between endogenous glucocorticoid metabolism and osteoblast function, we have characterized the expression of 11 beta-HSD isozymes in rat osteosarcoma cells [2].
• Patients with ectopic ACTH syndrome often develop hypertension and hypokalemic alkalosis with an abnormal increase in the ratio of plasma cortisol to cortisone, indicating that 11 beta-hydroxysteroid dehydrogenase (11 beta HSD) activity is inhibited [3].
• The objective of this study was to investigate whether 11 beta-HSD contributes to the occurrence of hypertension in spontaneously hypertensive rats (SHRs) [4].
• This may be congenital as in the apparent mineralocorticoid excess syndrome or acquired secondary to liquorice-induced inhibition of 11 beta-OHSD [5].

High impact information on Hsd11b1

• CONCLUSIONS: These findings indicate that in liver cirrhosis the mineralocorticoid and glucocorticoid receptor-protecting effects by the 11 beta-OHSD isoenzymes are down-regulated and that by the same mechanism the glucocorticoid and mineralocorticoid effects are enhanced [6].
• Down-regulation of hepatic and renal 11 beta-hydroxysteroid dehydrogenase in rats with liver cirrhosis [6].
• Increased fetal glucocorticoid exposure secondary to attenuated placental 11 beta-OHSD activity may link low birthweight and high placental weight with hypertension [7].
• Offspring of rats treated during pregnancy with dexamethasone (which is not metabolised by 11 beta-OHSD) had lower birthweights and higher blood pressure when adult than did offspring of control rats [7].
• We found that rat placental 11 beta-OHSD activity correlated positively with term fetal weight and negatively with placental weight [7].

Chemical compound and disease context of Hsd11b1

• A search of sequence databases revealed that 11-DH is identical in about 27% of amino acid residues to ribitol dehydrogenase from Klebsiella and to the product of the nodG gene from the nitrogen-fixing bacterium, Rhizobium meliloti, thus defining a new superfamily of genes encoding dehydrogenases [8].
• These results show that both 3 alpha,5B-THP and CDCA are hypertensinogenic in the rat and that the inhibition of either 11 beta-HSD2 or 11 beta-HSD1 activity by endogenous progesterone metabolites and CDCA may be involved in the pathology of hypertension [9].
• Here, we show that maternal administration of carbenoxolone, a potent inhibitor of 11 beta-HSD, throughout pregnancy leads to reduced birth weight (mean 20 percent decrease) and elevated blood pressures (increase in mean arterial pressure, 9 mm Hg in males, 7 mm Hg in females) in the adult offspring of carbenoxolone-treated rats [10].
• Readily metabolized endogenous glucocorticoids produced little or no effect on developing heart muscle while treatment with dexamethasone, a potent synthetic glucocorticoid, induced relative cardiac hypertrophy and downregulated 11 beta-OHSD mRNA expression and enzyme activity [11].
• A novel 11 beta-hydroxysteroid dehydrogenase inhibitor contained in saiboku-to, a herbal remedy for steroid-dependent bronchial asthma [12].

Biological context of Hsd11b1

• Regulation of sodium-potassium adenosine triphosphate subunit gene expression by corticosteroids and 11 beta-hydroxysteroid dehydrogenase activity [13].
• Cell transfection by a lipofection method did not alter 11 beta-HSD activity in LLC-PK1 cells [14].
• LLC-PK1 cell 11 beta-HSD activity was inhibited by carbenoxolone (IC50 approximately 10(-8) M) and high concentrations of estradiol or progesterone (10(-7) and 10(-6) M), but was induced at lower estradiol concentrations (10(-8) and 10(-9) M) [14].
• Carbenoxolone treatment of hMR-transfected CV-1 cells did not result in a shift of the dose-response transactivation curves of B and F toward lower concentrations, ruling out the implication of 11HSD in the aldosterone MR selectivity of these conditions [15].
• We have analyzed the kinetics of 11 beta-HSD activity in human kidney and compared it with the expressed human type I 11 beta-HSD cDNA [16].

Anatomical context of Hsd11b1

• Epithelial cell localization of type 2 11 beta-hydroxysteroid dehydrogenase in rat and human colon [17].
• Both isoforms of 11 beta HSD were detected in rat and human colonic mucosa [17].
• We have screened clonal mammalian cell lines for 11 beta-HSD activity [14].
• Vascular smooth muscle cells (VSMC) express MR and 11 beta HSD1/2, with 11 beta HSD1 reported to show uncharacteristic oxidase activity, so that VSMC thus constitute a potential physiologic aldosterone target tissue [1].
• Pig kidney epithelial LLC-PK1 cells expressed by far the greatest 11 beta-HSD activity [14].

Associations of Hsd11b1 with chemical compounds

• This has been suggested to reflect the action of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD), which catalyzes rapid inactivation of corticosterone to 11-dehydrocorticosterone (cortisol to cortisone) [14].
• Cultured rat kidney epithelial cells (NRK 52-E) expressed 11 beta HSD activity, which was inhibited by the licorice derivative glycyrrhetinic acid (GE) [13].
• Glycyrrhizic acid also inhibited both renal 11 beta HSD mRNA and activity and levels of Na,K-ATPase alpha 1/beta 1 mRNA [13].
• Colonic type 2 11 beta HSD is kinetically distinct from the low affinity NADP-dependent type I isoform, behaves predominantly as a dehydrogenase, is localized exclusively to the ion-transporting epithelia, and is likely to be the product of a second 11 beta HSD gene [17].
• 11 Beta-hydroxysteroid dehydrogenase (11 beta-HSD) catalyses the interconversion of active corticosterone and inert 11-dehydrocorticosterone [18].

Co-localisations of Hsd11b1

• We have previously demonstrated (Bonvalet et al, J Clin Invest 86:832-837, 1990) that 11 beta-OHSD is colocalized with MR along the rabbit nephron [19].

Other interactions of Hsd11b1

• In epithelial tissues such as kidney, mineralocorticoid receptors (MR) are protected against glucocorticoid occupancy by the enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta HSD) type 2 [1].
• Analysis of mRNA from ROS 25/1, UMR 106 and ROS 17/2.8 cells revealed transcripts for both 11 beta-HSD type 1 (11 beta-HSD1) and type 2 (11 beta-HSD2) in all three cell lines [2].
• In the rat, however, 11 beta-OHSD mRNA and activity is widespread, suggesting that it may also play a role in regulating ligand access to the glucocorticoid receptor (GR) [20].
• The time course of the T3 effect in liver and pituitary in vivo and the lack of any effect in vitro suggests that this action is indirect, and not as a result of interaction between the T3 receptor and the putative thyroid hormone response element on the rat 11 beta-HSD gene [21].
• We have studied the role of the 11 beta-OHSD in modulating corticosteroid hormone action in rat pituitary GH3 cells (glucocorticoids inhibit prolactin gene transcription) and renal epithelial NRK-52E cells (mineralocorticoids increase Na-K ATPase subunit gene expression) in culture [20].

Analytical, diagnostic and therapeutic context of Hsd11b1

• Northern blot analysis of rat colonic RNA using a 32P-labeled complementary DNA probe for rat type I 11 beta HSD confirmed the presence of type I 11 beta HSD messenger RNA in intact distal colon mucosa, but failed to detect 11 beta HSD messenger RNA in surface epithelial cells [17].
• We have now analyzed the expression and activity of 11 beta HSD in specific cells isolated from both rat and human colonic mucosa by a chemical shear and microdissection method [17].
• Both cell lines express high levels of 11 beta-OHSD activity, and Northern/Western blot analyses using a rat cDNA probe and antisera raised against rat liver 11 beta-OHSD reveal a single 1.4 Kb mRNA encoding an enzyme of molecular size 34 kDa [20].
• The catalytic activity of 11HSD was analyzed using HPLC by measuring the tritiated metabolites produced in CV-1 and COS cells [15].
• Southern blot analysis of rat and human DNA suggested that additional genes related to 11-DH exist in both species [8].

References