Influence of placental 11β-hydroxysteroid dehydrogenase (11β-HSD) inhibition on glucose metabolism and 11β-HSD regulation in adult offspring of rats

Placental 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) converts glucocorticoids to 11-keto-products and is believed to play an important role in protecting fetuses from higher maternal glucocorticoid levels. Recent reports have speculated that prenatal glucocorticoid exposure leads to fetal growth retardation and adult offspring hypertension and hyperglycemia. To investigate the effects of placental 11β-HSD2 inhibition on glucose metabolism and the 11β-HSD system in adult offspring, pregnant rats were treated with daily injections of carbenoxolone (CBX), an inhibitor of 11β-HSD. The offspring of the maternal CBX treatment group showed reduced birth weight (treated v control, 5.6 ± 0.5 v 6.4 ± 0.4 g, P < .0001). In adult offspring of the maternal CBX treatment group, plasma hemoglobin A_1c was significantly increased (7.3% ± 1.8% v 4.8% ± 0.3%, P < .01) and glucose intolerance was shown on the oral glucose tolerance test. The gene expression of hepatic 11β-HSD1 and renal 11β-HSD2 was decreased 87.6% (P < .05) and 52.3% (P < .01) in adult offspring of the maternal CBX treatment group, whereas renal 11β-HSD1 was not significantly altered. The change in 11β-HSD activity corresponded to the change in the gene expression. These results suggest that inhibition of placental 11β-HSD2 causes growth retardation, glucose intolerance, and partial suppression of the 11β-HSD system in the offpsring.     

Different responsiveness in body weight and hepatic 11beta-hydroxysteroid dehydrogenase (11beta-HSD) type 1 mrna to 11beta-HSD inhibition by glycyrrhetinic acid treatment in obese and lean zucker rats

Tissue-specific dysregulation of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) activity in obese humans and animals may be associated with obesity and the metabolic syndrome. We investigated the effect of inhibition of 11beta-HSD with glycyrrhetinic acid (GE), an effective 11beta-HSD inhibitor, on body weight regulation in obese Zucker rats, which have a defect in the leptin receptor gene. GE (280 mg/kg/d) was administered in drinking water to 8-week-old male Zucker rats for 14 weeks. GE had no effect on food intake or weight gain, and did not affect hepatic 11beta-HSD1 and renal 11beta-HSD2 mRNA levels in obese rats. In contrast, average daily food intake and body weight on week 14 were significantly reduced by GE in lean rats (both P <.0001). Hepatic 11beta-HSD1 and renal 11beta-HSD2 mRNA levels were also significantly decreased by GE in lean rats (both P <.05). GE had no significant effect on plasma corticosterone levels in obese rats but lowered them in lean rats (P <.05). Plasma leptin levels declined in both GE-treated obese and lean rats (both P <.01). In conclusion, long-term GE treatment decreased weight gain in lean Zucker rats but not in obese Zucker rats. These findings suggest that the differing responses of 11beta-HSD1 to GE in obese and lean Zucker rats are closely associated with the different weight-gain responses. Furthermore, the weight-lowering effect of GE may require intact leptin receptors.     

Age-dependent decrease in 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) activity in hypertensive patients

BACKGROUND: The prevalence of arterial hypertension lacking a defined underlying cause increases with age. Age-related arterial hypertension is insufficiently understood, yet known characteristics suggest an aldosterone-independent activation of the mineralocorticoid receptor. Therefore, we hypothesized that 11beta-HSD2 activity is age-dependently impaired, resulting in a compromised intracellular inactivation of cortisol (F) with F-mediated mineralocorticoid hypertension. METHODS: Steroid hormone metabolites in 24-h urine samples of 165 consecutive hypertensive patients were analyzed for F and cortisone (E), and their TH-metabolites tetrahydro-F (THF), 5alphaTHF, TH-deoxycortisol (THS), and THE by gas chromatography-mass spectroscopy. Apparent 11beta-HSD2 and 11beta-hydroxylase activity and excretion of F metabolites were assessed. RESULTS: In 72 female and 93 male patients aged 18-84 years, age correlated positively with the ratios of (THF + 5alphaTHF)/THE (P = 0.065) and F/E (P < 0.002) suggesting an age-dependent reduction in the apparent 11beta-HSD2 activity, which persisted (F/E; P = 0.020) after excluding impaired renal function. Excretion of F metabolites remained age-independent most likely as a consequence of an age-dependent diminished apparent 11beta-hydroxylase activity (P = 0.038). CONCLUSION: Reduced 11beta-HSD2 activity emerges as a previously unrecognized risk factor contributing to the rising prevalence of arterial hypertension in elderly. This opens new perspectives for targeted treatment of age-related hypertension.     

Oxygen regulation of placental 11 beta-hydroxysteroid dehydrogenase 2: physiological and pathological implications

Preeclampsia (PE) is a major cause of maternal and perinatal morbidity and mortality. The genesis of PE is related to deficient trophoblast invasion of maternal spiral arteries, which might result in a reduction of placental (PL) oxygen (O(2)). An absence of increased O(2) that normally occurs around the 10-12th wk of gestation results in aberrant expression of genes that might contribute to the pathophysiology of PE. We examined the expression and regulation of PL 11 beta-hydroxysteroid dehydrogenase 2 (11 beta-HSD) in normal pregnancies and in PE. Two types of 11 beta-HSD exist in the placenta, 11 beta-HSD1 and 11 beta-HSD2. 11 beta-HSD2 is thought to protect the fetus from cortisol excess. In PE, both the expression and activity of PL 11 beta-HSD2 were reduced significantly compared with those in age-matched controls. As PE is associated with a reduction of PL O(2), we next investigated whether in normal pregnancy 11 beta-HSD2 expression changes at the time of the increase in O(2). 11 beta-HSD2 was detected as early as 5 wk, with expression limited to the syncytiotrophoblast (ST). At 10-12 wk, this expression increased and was also found in the cytotrophoblast and extravillous trophoblast. These results were substantiated by Western blot. The ability of O(2) to regulate 11 beta-HSD2 was determined both in cultures of villous explant from early gestation and in term trophoblast cells after incubation under 3% or 20% O(2). Villous explants cultured under 20% O(2) showed higher enzyme activity and expression compared with 3% O(2). Term trophoblast cells also exhibited higher enzyme activity at 20% vs. 3% O(2). No change in 11 beta-HSD1 expression was observed in early pregnancy or in PE. This is the first report to suggest that 11 beta-HSD2 is O(2) dependent in first and third trimester placenta during human gestation.     

Two elderly patients with mineralocorticoid excess due to 11 beta-hydroxysteroid dehydrogenase type 2 (11 beta-HSD2) impairment

A 75-year-old woman had a low circulating level of aldosterone, despite the mineralocorticoid excess state. These abnormalities were improved by spironolactone administration. The distinct elevation of urinary cortisol/cortisone ratio revealed 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) impairment. Moreover, slight but distinct elevation of the ratio was found in a 95-year-old woman with normotension and normopotassemia. The mineralocorticoid excess state with reduced aldosterone level appeared following with vomiting and diarrhea, exaggerating asymptomatic impairment of 11beta-HSD2 to induce apparent mineralocorticoid excess (AME)-like condition.     

Altered placental function of 11beta-hydroxysteroid dehydrogenase 2 knockout mice

Fetal glucocorticoid exposure is a key mechanism proposed to underlie prenatal "programming" of adult cardiometabolic and neuropsychiatric disorders. Regulation of fetal glucocorticoid exposure is achieved by the placental glucocorticoid "barrier," which involves glucocorticoid inactivation within the labyrinth zone of the murine placenta by 11beta-hydroxysteroid dehydrogenase 2 (11beta-HSD2). Thus, the absence of placental 11beta-HSD2 may impact on fetal and placental development. The current study investigated transport of amino acids and glucose, key factors required for fetal growth, and vascular development in placentas from 11beta-HSD2(+/+), (+/-), and (-/-) fetuses derived from 11beta-HSD2(+/-) matings. At embryonic d 15 (E15) (term = E19), 11beta-HSD2(-/-) fetal weight was maintained in comparison to 11beta-HSD2(+/+) fetuses. The maintenance of 11beta-HSD2(-/-) fetal weight occurred despite a reduction in placental weight, suggesting that compensatory changes occur in the placenta to maintain function. However, by E18, 11beta-HSD2(-/-) fetal and placental weights were both reduced. Transport studies revealed up-regulation of placental amino acid transport to 11beta-HSD2(-/-) offspring at E15, coinciding with an increase in the expression of the amino acid transporters. Furthermore, at E18, placental glucose transport to 11beta-HSD2(-/-) offspring was markedly reduced, correlating with lower fetal weight and a decrease in glucose transporter 3 expression. Stereological analyses of the labyrinth zone of the placenta revealed that the reduction in placental weight at E18 was associated with restriction of the normal increase in fetal vessel density over the final third of pregnancy. Our data suggest that restriction of fetal growth in 11beta-HSD2(-/-) mice is mediated, at least in part, via altered placental transport of nutrients and reduction in placental vascularization.     

Cortisol metabolism and the role of 11beta-hydroxysteroid dehydrogenase

Two isoforms of the enzyme 11beta-hydroxysteroid dehydrogenase (11beta-HSD) interconvert the active glucocorticoid, cortisol, and inactive cortisone. 11beta-HSD1 is believed to act in vivo predominantly as an oxo-reductase using NADP(H) as a cofactor to generate cortisol. In contrast, 11beta-HSD2 acts exclusively as an NAD-dependent dehydrogenase inactivating cortisol to cortisone, thereby protecting the mineralocorticoid receptor from occupation by cortisol. In peripheral tissues, both enzymes serve to control the availability of cortisol to bind to the corticosteroid receptors. Defective expression of 11beta-HSD2 is implicated in patients with hypertension and intra-uterine growth retardation, while 11beta-HSD1 appears to be intricately involved in the conditions of apparent cortisone reductase deficiency, insulin resistance and visceral obesity.The ability of peripheral tissues to regulate corticosteroid concentrations through 11beta-HSD isozymes is established as an important mechanism in the pathogenesis of diverse human diseases. Modulation of enzyme activity may offer a novel therapeutic approach to treating human disease while circumventing the consequences of systemic glucocorticoid excess or deficiency.     

Selective inhibition of 11beta-hydroxysteroid dehydrogenase type 1 decreases blood glucose concentrations in hyperglycaemic mice

AIMS/HYPOTHESIS: Current pharmacological treatments for Type II (non-insulin-dependent) diabetes mellitus have various limitations. New treatments are needed to reduce long-term risks for diabetic complications and mortality. We tested a new principle for lowering blood glucose. It is well known that glucocorticoids in excess cause glucose intolerance and insulin resistance. The enzymes 11beta-hydroxysteroid dehydrogenase type 1 and type 2 inter-convert inactive and active glucocorticoids, thereby playing a major role in local modulation of agonist concentration and activation of corticosteroid receptors in target tissues. It has been hypothesized that selective inhibition of 11beta-hydroxysteroid dehydrogenase type 1 decreases excessive hepatic glucose production in hyperglycemia and diabetes. BVT.2733 is a new, small molecule, non-steroidal, isoform-selective inhibitor of mouse 11beta-hydroxysteroid dehydrogenase type 1. The aim of the present study is to test if selective inhibition of 11beta-hydroxysteroid dehydrogenase type 1 lowers blood glucose concentrations in a hyperglycaemic and hyperinsulinaemic mouse model. METHODS: BVT.2733 was given to spontaneously hyperglycaemic KKA(y) mice for 7 days using subcutaneous osmotic mini-pumps. RESULTS: BVT.2733 lowered hepatic PEPCK and glucose-6-phosphatase mRNA, blood glucose and serum insulin concentrations compared with vehicle treated mice. In contrast, hepatic 11beta-hydroxysteroid dehydrogenase type 1 mRNA, liver function marker enzyme expression (aspartate aminotransferase, alanine aminotransferase and alkaline phosphatases), daily food intake and body weight were not altered by the treatment. CONCLUSION/INTERPRETATION: These results suggest that a selective inhibitor of human 11beta-hydroxysteroid dehydrogenase type 1 can become a new approach for lowering blood glucose concentrations in Type II diabetes.     

A rapid screening assay for inhibitors of 11beta-hydroxysteroid dehydrogenases (11beta-HSD): flavanone selectively inhibits 11beta-HSD1 reductase activity

A rapid screening assay for chemicals inhibiting 11beta-hydroxysteroid dehydrogenase (11beta-HSD) type 1 or type 2 using lysates from stably transfected cells was developed. Here, we tested a series of environmental chemicals for anti-11beta-HSD activities. Inhibition of 11beta-HSD2, which may cause cortisol-dependent activation of the mineralocorticoid receptor with sodium retention and hypertension, was observed for several compounds, with diethylcarbamate being the most potent inhibitor (IC50 6.3 microM). Abietic acid inhibited both 11beta-HSD1 (IC50 27 microM for reduction and 2.8 microM for oxidation) and 11beta-HSD2 (IC50 12 microM). Our results demonstrate for the first time that flavanone selectively inhibits 11beta-HSD1 reductase activity: this enzyme being considered as essential for the local activation of glucocorticoids and representing a potential target for the therapeutic treatment of diabetes type 2. Flavanone and 2'-hydroxyflavanone efficiently inhibited reductive (IC50 18 and 10 microM) but not oxidative activity. We observed a reduced inhibitory effect of hydroxylated flavanone derivatives and of flavones containing a double-bond between atom C2 and C3. Flavanone was specific for 11beta-HSD1 and did not inhibit 11beta-HSD2. Our results reveal that a variety of environmental compounds exert distinct inhibitory effects on 11beta-HSD1 and 11beta-HSD2, opening the possibility for selectively modulating local cortisone/cortisol availability in vivo.     

Intracellular regeneration of glucocorticoids by 11beta-hydroxysteroid dehydrogenase (11beta-HSD)-1 plays a key role in regulation of the hypothalamic-pituitary-adrenal axis: analysis of 11beta-HSD-1-deficient mice

11beta-Hydroxysteroid dehydrogenases (11beta-HSDs) catalyze interconversion of active corticosterone and inert 11-dehydrocorticosterone, thus regulating glucocorticoid access to intracellular receptors in vivo. 11beta-HSD type 1 is a reductase, locally regenerating active glucocorticoids. To explore the role of this isozyme in the brain, we examined hypothalamic-pituitary-adrenal axis (HPA) regulation in mice homozygous for a targeted disruption of the 11beta-HSD-1 gene. 11beta-HSD-1-deficient mice showed elevated plasma corticosterone and ACTH levels at the diurnal nadir, with a prolonged corticosterone peak, suggesting abnormal HPA control and enhanced circadian HPA drive. Despite elevated corticosterone levels, several hippocampal and hypothalamic glucocorticoid-sensitive messenger RNAs were normally expressed in 11beta-HSD-1-deficient mice, implying reduced effective glucocorticoid activity within neurons. 11beta-HSD-1-deficient mice showed exaggerated ACTH and corticosterone responses to restraint stress, with a delayed fall after stress, suggesting diminished glucocorticoid feedback. Indeed, 11beta-HSD-1-deficient mice were less sensitive to exogenous cortisol suppression of HPA activation. Thus 11beta-HSD-1 amplifies glucocorticoid feedback on the HPA axis and is an important regulator of neuronal glucocorticoid exposure under both basal and stress conditions in vivo.     

The regulation and inhibition of 17beta-hydroxysteroid dehydrogenase in breast cancer

17Beta-hydroxysteroid dehydrogenase Type 1 (17beta-HSD1) has a pivotal role in regulating the synthesis of oestradiol (E2) within breast tumours. In whole body studies in postmenopausal women with breast cancer the conversion of oestrone (E1) to E2 (4.4+/-1.1%) was much lower than the inactivation of E2 to E1 (17.3+/-5.0%). In contrast, an examination of in vivo oestrogen metabolism within breast tumours revealed that whereas little metabolism of E2 occurred, E1 was converted to E2 to a much greater extent in malignant (48+/-14%) than in normal (19+/-6%) breast tissue. Findings from these studies originally suggested that oestrogen metabolism within breast tumours may differ from the mainly oxidative direction found in most other body tissues and that the activity of 17beta-HSD1 might be regulated by tumour-derived factors. Several growth factors (e.g. IGF-I, IGF-II) and cytokines (e.g. IL-6, TNFalpha) have now been identified which can markedly stimulate the activity of 17beta-HSD1 and such a mechanism may account for the high concentrations of E2 found in most breast tumours. Cells of the immune system, which can infiltrate breast tumours, are thought to be a major source of the growth factors and cytokines which can modulate 17beta-HSD1 activity. Given the central role that 17beta-HSD1 has in regulating breast tumour E2 concentrations the development of potent inhibitors of this enzyme has recently attracted considerable attention. Our initial studies in this area explored the use of derivatives of E1 as inhibitors, with 2-ethyl- and 2-methoxy E1 being found to inhibit 17beta-HSD1 activity in T-47D breast cancer cells by 96+/-2 and 91+/-1% respectively at 10 microM, but with a lack of specificity. Using the E1 scaffold a number of potent, selective 17beta-HSD1 inhibitors have now been identified including E1- and 2-ethyl-E1 containing a side chain with a m-pyridylmethylamidomethyl functionality extending from the 16beta position of the steroid nucleus. At 10 microM these compounds both inhibited 17beta-HSD1 activity by >90%, however some inhibition of 17beta-HSD2 activity was exhibited by the E1 derivative (25%) but not the 2-ethyl analogue. It is now apparent that 17beta-HSD1 activity contributes to the high E2 concentrations found in most breast tumours. The identification of potent, selective novel 17beta-HSD1 inhibitors will allow their efficacy to be tested in in vitro and in vivo studies.     

11beta-hydroxysteroid dehydrogenase and corticosteroid action in lyon hypertensive rats

Adrenocorticosteroid activity in Lyon hypertensive (LH) and low blood pressure (LL) rat strains differ in several respects. Abnormal activity of 11beta-hydroxysteroid dehydrogenase enzymes (11beta-HSD1 and 11beta-HSD2), which interconvert corticosterone and inactive 11-dehydrocorticosterone, might contribute to the LH phenotype by regulating corticosteroid hormone access to receptors. 11beta-HSD2 (expressed in kidney but not liver) prevents endogenous glucocorticoids from binding to mineralocorticoid receptors. 11beta-HSD1 (expressed in liver and kidney) favors active glucocorticoid formation from 11-dehydrocorticosterone. 11beta-HSD properties in LH and LL have been compared by several approaches: (1) 11betaHSD activities have been measured in vitro as corticosterone dehydrogenation and in vivo as interconversion of injected cortisol and cortisone; (2) the effects of cortisol and cortisone on urine electrolytes and volume have been measured; and (3) 11beta-HSD mRNA expression has been measured by in situ hybridization. 11beta-HSD2 enzyme activities in LH and LL rats were similar and urinary cortisone:cortisol ratios were not different after cortisol injection. Cortisol caused a natriuresis and kaliuresis in both strains, with a slightly reduced response in LH rats. Renal 11beta-HSD2 mRNA expression was slightly lower in LH rats. 11beta-HSD1 was less active in LH than LL rats: enzyme activities were lower in tissue extracts; urinary cortisone:cortisol was lower in LL rats after cortisone injections; cortisone increased urine volume in LL but not LH rats; and mRNA levels tended to be lower in LH tissues. We conclude that 11beta-HSD1 is impaired in LH rats. The LH phenotype of heavier adrenals, raised corticosterone, and reduced thymus weight is similar to that described for 11beta-HSD1 knockout mice.     

11beta-hydroxysteroid dehydrogenase and the pre-receptor regulation of corticosteroid hormone action

Two isozymes of 11beta-hydroxysteroid dehydrogenase (11beta-HSD1 and 11beta-HSD2) catalyse the interconversion of hormonally active cortisol and inactive cortisone. The enzyme evolved from a metabolic pathway to a novel mechanism underpinning human disease with the elucidation of the role of the type 2 or 'kidney' isozyme and an inherited form of hypertension, 'apparent mineralocorticoid excess'. 'Cushing's disease of the kidney' arises because of a failure of 11beta-HSD2 to inactivate cortisol to cortisone resulting in cortisol-induced mineralocorticoid excess.Conversely, 11beta-HSD1 has been linked to human obesity and insulin resistance, but also to other diseases in which glucocorticoids have historically been implicated (osteoporosis, glaucoma). Here, the activation of cortisol from cortisone facilitates glucocorticoid hormone action at an autocrine level. The molecular basis for the putative human 11beta-HSD1 'knockout'--'cortisone reductase deficiency'--has recently been described, an observation that also answers a long standing conundrum relating to the set-point of 11beta-HSD1 activity. In each case, these clinical studies have been underpinned by studies in vitro and the manipulation of enzyme expression in vivo using recombinant mouse models.     

Progesterone metabolism in the human kidney and inhibition of 11beta-hydroxysteroid dehydrogenase type 2 by progesterone and its metabolites

Progesterone binds with high affinity to the mineralocorticoid (MC) receptor, but confers only very low agonistic MC activity. Therefore, progesterone is a potent MC antagonist in vitro. Although progesterone reaches up to 100 times higher plasma levels in late pregnancy than aldosterone, the in vivo MC antagonistic effect of progesterone seems to be relatively weak. One explanation for this phenomenon could be local metabolism of progesterone in the human kidney, similar to the inactivation of cortisol to cortisone by the 11beta-hydroxysteroid dehydrogenase (11beta-HSD) type 2. We studied the metabolism of progesterone in the human kidney in vitro and found reduction to 20alpha-dihydro (DH)-progesterone as the main metabolite. Ring-A reduction to 5alpha-DH-progesterone, 20alpha-DH-5alpha-DH-progesterone, and 3beta,5alpha-tetrahydro (TH)-progesterone was also documented. We further showed for the first time that 17-hydroxylation of progesterone (17alpha-OH-progesterone, 17alpha-OH, 20alpha-DH-progesterone), normally localized in the adrenals and the gonads, occurs in the human adult kidney. We found no formation of deoxycorticosterone from progesterone in the human adult kidney. Using human kidney cortex microsomes, we tested the inhibitory potency of progesterone and its metabolites on the 11beta-HSD type 2. The most potent inhibitor was progesterone itself (IC50 = 4.8 x 10(-8) mol/L), followed by 5alpha-DH-progesterone (IC50 = 2.4 x 10(-7) mol/L), 20alpha-DH-progesterone, 3beta,5alpha-TH-progesterone, 17alpha-OH-progesterone, and 20alpha-DH-5alpha-DH-progesterone (IC50 between 7.7 x 10(-7) mol/L and 1.3 x 10(-6) mol/L). The least potent inhibitor was 17alpha-OH,20alpha-DH-progesterone. In addition to progesterone metabolism by the kidney, the inhibition of 11beta-HSD type 2 by progesterone and its metabolites could be a second explanation for the weak MC-antagonist activity of progesterone in vivo. Inhibition of 11beta-HSD type 2 leads to an increase of intracellular cortisol in a way that the local equilibrium between the MC agonist cortisol and the antagonist progesterone is shifted to the agonist side.     

The murine 3beta-hydroxysteroid dehydrogenase (3beta-HSD) gene family: a postulated role for 3beta-HSD VI during early pregnancy

The enzyme 3beta-hydroxysteroid dehydrogenase/isomerase (3beta-HSD) is essential for the biosynthesis of all active steroid hormones. The 3beta-HSD enzyme consists in multiple isoforms, each the product of a distinct gene. In the mouse, six tissue-specific isoforms have been identified. These isoforms are expressed in a tissue- and temporal specific manner. Mouse 3beta-HSD VI is the only isoform expressed in decidua and giant trophoblast cells during the first half of mouse pregnancy. The tissue- and temporal-specific expression of 3beta-HSD VI during mouse pregnancy, as determined by in situ hybridization and immunohistochemistry, shows that 3beta-HSD is expressed exclusively in the antimesometrial decidua on E6.5 and E7.5. By E9.5, expression of 3beta-HSD is observed in giant trophoblast cells with a marked increase in expression by E10.5. No expression of 3beta-HSD is seen in decidua after E7.5 and no expression of 3beta-HSD is seen in the embryo at any of the times investigated. Giant trophoblast cells in culture from E9.5 and E10.5 synthesize progesterone with cells from E10.5 producing about 3.5-fold more progesterone during the first 24 h in culture. Western blot analysis of 3beta-HSD VI protein demonstrates that the amount of 3beta-HSD VI protein correlates with the amount of progesterone biosynthesis in giant trophoblast cells from E9.5 and E10.5. We propose that progesterone produced during the first half of mouse pregnancy in decidua and giant trophoblast cells acts as an immunosuppressant at the fetal maternal interface to prevent rejection of the fetus.     

Sexual dimorphism of 11beta-hydroxysteroid dehydrogenase in hypertensive and normotensive rats.

To evaluate the role of sexually dimorphic tissue expression of 11beta-oxidase activity of 11beta-hydroxysteroid dehydrogenase (11betaHSD) in gender-associated blood pressure differences, we have studied female and male hypertensive rats of two different strains and their normotensive controls: spontaneously hypertensive rats (SHR), Wistar-Kyoto rats (WKY) and Dahl salt-sensitive (SS/Jr) and salt-resistant rats (SR/Jr). In hypertensive SHR and SS/Jr, but not in normotensive strains WKY and SR/Jr, blood pressure reached a higher level in males than in females. The activity of 11betaHSD was higher in the renal cortex, medulla, colon and aorta of males than of females in all investigated strains with the exception of aortic 11betaHSD in SHR and WKY rats, both of which had very low 11beta-oxidase activity. In contrast to gender-dependent differences, strain differences of 11betaHSD were observed in a limited number of tissues only. Renal medullary 11betaHSD showed significantly lower activity in WKY than in SHR, whereas no difference was observed in the renal cortex. Similarly, colonic 11betaHSD activity was lower in WKY than in SHR. In Dahl rats the strain differences were observed in aortic 11betaHSD that had higher activity in SR/Jr than in SS/Jr rats; no difference was observed in the kidney or colon. These data demonstrate the following. 1) Sexual dimorphism of 11betaHSD activity exists in the kidney, colon, and aorta. 2) The sexual dimorphism of 11betaHSD does not play a role in gender-associated differences in blood pressure. 3) The reduced 11betaHSD activity in the aorta of hypertensive SS/Jr compared to SR/Jr rats suggests that this enzyme might play a role in the pathogenesis of salt-sensitive hypertension in Dahl rats.     

Course of placental 11beta-hydroxysteroid dehydrogenase type 2 and 15-hydroxyprostaglandin dehydrogenase mRNA expression during human gestation.

BACKGROUND: During human pregnancy, 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) plays an important role in protecting the fetus from high maternal glucocorticoid concentrations by converting cortisol to inactive cortisone. Furthermore, 11beta-HSD2 is indirectly involved in the regulation of the prostaglandin inactivating enzyme 15-hydroxyprostaglandin dehydrogenase (PGDH), because cortisol reduces the gene expression and enzyme activity of PGDH in human placental cells. OBJECTIVE: To examine developmental changes in placental 11beta-HSD2 and PGDH gene expression during the 2nd and 3rd trimesters of human pregnancies. METHODS: In placental tissue taken from 20 healthy women with normal pregnancy and 20 placentas of 17 mothers giving birth to premature babies, 11beta-HSD2 and PGDH mRNA expression was determined using quantitative real-time PCR. RESULTS: Placental mRNA expression of 11beta-HSD2 and PGDH increased significantly with gestational age (r=0.55, P=0.0002 and r=0.42, P=0.007). In addition, there was a significant correlation between the two enzymes (r=0.58, P<0.0001). CONCLUSIONS: In the course of pregnancy there is an increase in 11beta-HSD2 and PGDH mRNA expression in human placental tissue. This adaptation of 11beta-HSD2 prevents increasing maternal cortisol concentrations from transplacental passage and is exerted at the gene level. 11beta-HSD2 up-regulation may also lead to an increase in PGDH mRNA concentrations that, until term, possibly delays myometrial contractions induced by prostaglandins.     

Depot-specific modulation of rat intraabdominal adipose tissue lipid metabolism by pharmacological inhibition of 11beta-hydroxysteroid dehydrogenase type 1

The metabolic consequences of visceral obesity have been associated with amplification of glucocorticoid action by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) in adipose tissue. This study aimed to assess in a rat model of diet-induced obesity the effects of pharmacological 11beta-HSD1 inhibition on the morphology and expression of key genes of lipid metabolism in intraabdominal adipose depots. Rats fed a high-sucrose, high-fat diet were treated or not with a specific 11beta-HSD1 inhibitor (compound A, 3 mg/kg.d) for 3 wk. Compound A did not alter food intake or body weight gain but specifically reduced mesenteric adipose weight (-18%) and adipocyte size, without significantly affecting those of epididymal or retroperitoneal depots. In mesenteric fat, the inhibitor decreased (to 25-50% of control) mRNA levels of genes involved in lipid synthesis (FAS, SCD1, DGAT1) and fatty acid cycling (lipolysis/reesterification, ATGL and PEPCK) and increased (30%) the activity of the fatty acid oxidation-promoting enzyme carnitine palmitoyltransferase 1. In striking contrast, in the epididymal depot, 11beta-HSD1 inhibition increased (1.5-5-fold) mRNA levels of those genes related to lipid synthesis/cycling and slightly decreased carnitine palmitoyltransferase 1 activity, whereas gene expression remained unaffected in the retroperitoneal depot. Compound A robustly reduced liver triacylglycerol content and plasma lipids. The study demonstrates that pharmacological inhibition of 11beta-HSD1, at a dose that does not alter food intake, reduces fat accretion specifically in the mesenterical adipose depot, exerts divergent intraabdominal depot-specific effects on genes of lipid metabolism, and reduces steatosis and lipemia.