Publications (31)155.61 Total impact
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Article: Glucocorticoid receptor is required for fetal heart maturation.
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ABSTRACT: Glucocorticoids are vital for the structural and functional maturation of fetal organs, yet excessive fetal exposure is detrimental to adult cardiovascular health. To elucidate the role of glucocorticoid signalling in late gestation cardiovascular maturation, we have generated mice with conditional disruption of glucocorticoid receptor (GR) in cardiomyocytes and vascular smooth muscle cells using smooth muscle protein 22-driven Cre recombinase (SMGRKO mice) and compared them to mice with global deficiency in GR (GR(-/-)). Echocardiography shows impaired heart function in both SMGRKO and GR(-/-) mice at embryonic day (E)17.5, associated with generalised edema. Cardiac ultrastructure is markedly disrupted in both SMGRKO and GR(-/-) mice at E17.5, with short, disorganised myofibrils and cardiomyocytes that fail to align in the compact myocardium. Failure to induce critical genes involved in contractile function, calcium handling and energy metabolism underpins this common phenotype. However, although hearts of GR(-/-) mice are smaller, with 22% reduced ventricular volume at E17.5, SMGRKO hearts are normally sized. Moreover, whilst levels of mRNA encoding atrial natriuretic peptide are reduced in E17.5 GR(-/-) hearts, they are normal in fetal SMGRKO hearts. These data demonstrate that structural, functional and biochemical maturation of the fetal heart is dependent on glucocorticoid signalling within cardiomyocytes and vascular smooth muscle, though some aspects of heart maturation (size, ANP expression) are independent of GR at these key sites.Human Molecular Genetics 04/2013; · 7.64 Impact Factor -
Article: A urine-concentrating defect in 11β-hydroxysteroid dehydrogenase type 2 null mice.
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ABSTRACT: In aldosterone target tissues, 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) is coexpressed with mineralocorticoid receptors (MR) and protects the receptor from activation by glucocorticoids. Null mutations in the encoding gene, HSD11B2, cause apparent mineralocorticoid excess, in which hypertension is thought to reflect volume expansion secondary to sodium retention. Hsd11b2(-/-) mice are indeed hypertensive, but impaired natriuretic capacity is associated with significant volume contraction, suggestive of a urine concentrating defect. Water turnover and the urine concentrating response to a 24-h water deprivation challenge were therefore assessed in Hsd11b2(-/-) mice and controls. Hsd11b2(-/-) mice have a severe and progressive polyuric/polydipsic phenotype. In younger mice (∼2 mo of age), polyuria was associated with decreased abundance of aqp2 and aqp3 mRNA. The expression of other genes involved in water transport (aqp4, slc14a2, and slc12a2) was not changed. The kidney was structurally normal, and the concentrating response to water deprivation was intact. In older Hsd11b2(-/-) mice (>6 mo), polyuria was associated with a severe atrophy of the renal medulla and downregulation of aqp2, aqp3, aqp4, slc14a2, and slc12a2. The concentrating response to water deprivation was impaired, and the natriuretic effect of the loop diuretic bumetanide was lost. In older Hsd11b2(-/-) mice, the V2 receptor agonist desmopressin did not restore full urine concentrating capacity. We find that Hsd11b2(-/-) mice develop nephrogenic diabetes insipidus. Gross changes to renal structure are observed, but these were probably secondary to sustained polyuria, rather than of developmental origin.AJP Renal Physiology 05/2012; 303(4):F494-502. · 4.42 Impact Factor -
Article: Reconciling the nutritional and glucocorticoid hypotheses of fetal programming.
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ABSTRACT: Fetal growth restriction associates with increased risk of adult cardiometabolic and neuropsychiatric disorders. Both maternal malnutrition [notably a low-protein (LP) diet] and stress/glucocorticoid exposure reduce fetal growth and cause persisting abnormalities (programming) in adult offspring. Deficiency of placental 11β-hydroxysteroid dehydrogenase-2 (11β-HSD2), which inactivates glucocorticoids, is reduced by an LP diet and has been proposed as a unifying mechanism. Here, we explored the importance of glucocorticoids and placental 11β-HSD2 in dietary programming. Pregnant mice were fed a control or isocaloric LP diet throughout gestation. The LP diet first elevated fetal glucocorticoid levels, then reduced placental growth, and finally decreased fetal weight near term by 17%. Whereas the LP diet reduced placental 11β-HSD2 activity near term by ∼25%, consistent with previous reports, activity was increased between 20 and 40% at earlier ages, implying that glucocorticoid overexposure in LP fetuses occurs via 11β-HSD2-independent mechanisms. Consistent with this, heterozygous 11β-HSD2(+/-) crosses showed that although both LP and 11β-HSD2 deficiency reduced fetal growth, LP indeed acted independently of 11β-HSD2. Instead, the LP diet induced the fetal hypothalamic-pituitary-adrenal axis per se. Thus, maternal malnutrition and placental 11β-HSD2 deficiency act via distinct processes to retard fetal growth, both involving fetoplacental overexposure to glucocorticoids but from distinct sources.The FASEB Journal 02/2012; 26(5):1866-74. · 5.71 Impact Factor -
Article: Activation of thiazide-sensitive co-transport by angiotensin II in the cyp1a1-Ren2 hypertensive rat.
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ABSTRACT: Transgenic rats with inducible expression of the mouse Ren2 gene were used to elucidate mechanisms leading to the development of hypertension and renal injury. Ren2 transgene activation was induced by administration of a naturally occurring aryl hydrocarbon, indole-3-carbinol (100 mg/kg/day by gastric gavage). Blood pressure and renal parameters were recorded in both conscious and anesthetized (butabarbital sodium; 120 mg/kg IP) rats at selected time-points during the development of hypertension. Hypertension was evident by the second day of treatment, being preceded by reduced renal sodium excretion due to activation of the thiazide-sensitive sodium-chloride co-transporter. Renal injury was evident after the first day of transgene induction, being initially limited to the pre-glomerular vasculature. Mircoalbuminuria and tubuloinsterstitial injury developed once hypertension was established. Chronic treatment with either hydrochlorothiazide or an AT1 receptor antagonist normalized sodium reabsorption, significantly blunted hypertension and prevented renal injury. Urinary aldosterone excretion was increased ≈ 20 fold, but chronic mineralocorticoid receptor antagonism with spironolactone neither restored natriuretic capacity nor prevented hypertension. Spironolactone nevertheless ameliorated vascular damage and prevented albuminuria. This study finds activation of sodium-chloride co-transport to be a key mechanism in angiotensin II-dependent hypertension. Furthermore, renal vascular injury in this setting reflects both barotrauma and pressure-independent pathways associated with direct detrimental effects of angiotensin II and aldosterone.PLoS ONE 01/2012; 7(4):e36311. · 4.09 Impact Factor -
Article: Hsd11b2 haploinsufficiency in mice causes salt sensitivity of blood pressure.
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ABSTRACT: Salt sensitivity of blood pressure is an independent risk factor for cardiovascular morbidity. Mechanistically, abnormal mineralocorticoid action and subclinical renal impairment may blunt the natriuretic response to high sodium intake, causing blood pressure to rise. 11β-Hydroxysteroid dehydrogenase type 2 (11βHSD2) controls ligand access to the mineralocorticoid receptor, and ablation of the enzyme causes severe hypertension. Polymorphisms in HSD11B2 are associated with salt sensitivity of blood pressure in normotensives. In this study, we used mice heterozygote for a null mutation in Hsd11b2 (Hsd11b2(+/-)) to define the mechanisms linking reduced enzyme activity to salt sensitivity of blood pressure. A high-sodium diet caused a rapid and sustained increase in blood pressure in Hsd11b2(+/-) mice but not in wild-type littermates. During the adaptation to high-sodium diet, heterozygotes displayed impaired sodium excretion, a transient positive sodium balance, and hypokalemia. After 21 days of high-sodium feeding, Hsd11b2(+/-) mice had an increased heart weight. Mineralocorticoid receptor antagonism partially prevented the increase in heart weight but not the increase in blood pressure. Glucocorticoid receptor antagonism prevented the rise in blood pressure. In Hsd11b2(+/-) mice, high-sodium feeding caused suppression of aldosterone and a moderate but sustained increase in corticosterone. This study demonstrates an inverse relationship among 11βHSD2 activity, heart weight, and blood pressure in a clinically important context. Reduced activity causes salt sensitivity of blood pressure, but this does not reflect illicit activation of mineralocorticoid receptors by glucocorticoids. Instead, we have identified a novel interaction among 11βHSD2, dietary salt, and circulating glucocorticoids.Hypertension 03/2011; 57(3):515-20. · 6.21 Impact Factor -
Article: Dietary manipulation reveals an unexpected inverse relationship between fat mass and adipose 11β-hydroxysteroid dehydrogenase type 1.
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ABSTRACT: Increased dietary fat intake is associated with obesity, insulin resistance, and metabolic disease. In transgenic mice, adipose tissue-specific overexpression of the glucocorticoid-amplifying enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) exacerbates high-fat (HF) diet-induced visceral obesity and diabetes, whereas 11β-HSD1 gene knockout ameliorates this, favoring accumulation of fat in nonvisceral depots. Paradoxically, in normal mice HF diet-induced obesity (DIO) is associated with marked downregulation of adipose tissue 11β-HSD1 levels. To identify the specific dietary fats that regulate adipose 11β-HSD1 and thereby impact upon metabolic disease, we either fed mice diets enriched (45% calories as fat) in saturated (stearate), monounsaturated (oleate), or polyunsaturated (safflower oil) fats ad libitum or we pair fed them a low-fat (11%) control diet for 4 wk. Adipose and liver mass and glucocorticoid receptor and 11β-HSD1 mRNA and activity levels were determined. Stearate caused weight loss and hypoinsulinemia, partly due to malabsorption, and this markedly increased plasma corticosterone levels and adipose 11β-HSD1 activity. Oleate induced pronounced weight gain and hyperinsulinemia in association with markedly low plasma corticosterone and adipose 11β-HSD1 activity. Weight gain and hyperinsulinemia was less pronounced with safflower compared with oleate despite comparable suppression of plasma corticosterone and adipose 11β-HSD1. However, with pair feeding, safflower caused a selective reduction in visceral fat mass and relative insulin sensitization without affecting plasma corticosterone or adipose 11β-HSD1. The dynamic depot-selective relationship between adipose 11β-HSD1 and fat mass strongly implicates a dominant physiological role for local tissue glucocorticoid reactivation in fat mobilization.AJP Endocrinology and Metabolism 03/2011; 300(6):E1076-84. · 4.75 Impact Factor -
Article: A stratified transcriptomics analysis of polygenic fat and lean mouse adipose tissues identifies novel candidate obesity genes.
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ABSTRACT: Obesity and metabolic syndrome results from a complex interaction between genetic and environmental factors. In addition to brain-regulated processes, recent genome wide association studies have indicated that genes highly expressed in adipose tissue affect the distribution and function of fat and thus contribute to obesity. Using a stratified transcriptome gene enrichment approach we attempted to identify adipose tissue-specific obesity genes in the unique polygenic Fat (F) mouse strain generated by selective breeding over 60 generations for divergent adiposity from a comparator Lean (L) strain. To enrich for adipose tissue obesity genes a 'snap-shot' pooled-sample transcriptome comparison of key fat depots and non adipose tissues (muscle, liver, kidney) was performed. Known obesity quantitative trait loci (QTL) information for the model allowed us to further filter genes for increased likelihood of being causal or secondary for obesity. This successfully identified several genes previously linked to obesity (C1qr1, and Np3r) as positional QTL candidate genes elevated specifically in F line adipose tissue. A number of novel obesity candidate genes were also identified (Thbs1, Ppp1r3d, Tmepai, Trp53inp2, Ttc7b, Tuba1a, Fgf13, Fmr) that have inferred roles in fat cell function. Quantitative microarray analysis was then applied to the most phenotypically divergent adipose depot after exaggerating F and L strain differences with chronic high fat feeding which revealed a distinct gene expression profile of line, fat depot and diet-responsive inflammatory, angiogenic and metabolic pathways. Selected candidate genes Npr3 and Thbs1, as well as Gys2, a non-QTL gene that otherwise passed our enrichment criteria were characterised, revealing novel functional effects consistent with a contribution to obesity. A focussed candidate gene enrichment strategy in the unique F and L model has identified novel adipose tissue-enriched genes contributing to obesity.PLoS ONE 01/2011; 6(9):e23944. · 4.09 Impact Factor -
Article: Transcriptional and physiological responses to chronic ACTH treatment by the mouse kidney.
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ABSTRACT: We investigated the effects on urinary steroid and electrolyte excretion and renal gene expression of chronic infusions of ACTH in the mouse. ACTH caused a sustained increase in corticosteroid excretion; aldosterone excretion was only transiently elevated. There was an increase in the excretion of deoxycorticosterone, a weak mineralocorticoid, to levels of physiological significance. Nevertheless, we observed neither antinatriuresis nor kaliuresis in ACTH-treated mice, and plasma renin activity was not suppressed. We identified no changes in expression of mineralocorticoid target genes. Water turnover was increased in chronic ACTH-treated mice, as were hematocrit and hypertonicity: volume contraction is consistent with high levels of glucocorticoid. ACTH-treated mice exhibited other signs of glucocorticoid excess, such as enhanced weight gain and involution of the thymus. We identified novel ACTH-induced changes in 1) genes involved in vitamin D (Cyp27b1, Cyp24a1, Gc) and calcium (Sgk, Calb1, Trpv5) metabolism associated with calciuria and phosphaturia; 2) genes that would be predicted to desensitize the kidney to glucocorticoid action (Nr3c1, Hsd11b1, Fkbp5); and 3) genes encoding transporters of enzyme systems associated with xenobiotic metabolism and oxidative stress. Although there is evidence that ACTH-induced hypertension is a function of physiological cross talk between glucocorticoids and mineralocorticoids, the present study suggests that the major changes in electrolyte and fluid homeostasis and renal function are attributable to glucocorticoids. The calcium and organic anion metabolism pathways that are affected by ACTH may explain some of the known adverse effects associated with glucocorticoid excess.Physiological Genomics 11/2009; 40(3):158-66. · 2.73 Impact Factor -
Article: Physiological and pathophysiological applications of sensitive ELISA methods for urinary deoxycorticosterone and corticosterone in rodents.
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ABSTRACT: Deoxycorticosterone (DOC: a weak mineralocorticoid) is the precursor to corticosterone (B: the major glucocorticoid in rodents) and aldosterone (the major mineralocorticoid). The genes Cyp11b1 and Cyp11b2 that encode the enzymes responsible for DOC to B (11beta-hydroxylase) and DOC to aldosterone (aldosterone synthase) conversions are located on the same chromosome. The aim of this study was to develop sensitive and specific ELISA methods to quantify urinary DOC and B concentrations to assess the physiological and genetic control of the Cyp11b1/b2 locus. Antibodies raised in rabbits against DOC and B and horse radish peroxidase-goat anti-rabbit IgG enzyme tracer were used to develop the assays. Urine samples collected from mice held in metabolic cages were extracted with dichloromethane and reconstituted in assay buffer. The assays were validated for specificity, sensitivity, parallelism, accuracy and imprecision. Cross-reactivities with major interfering steroids were minimal: DOC assay (progesterone=0.735% and corticosterone=0.045%), and for B assay (aldosterone=0.14%, 11-dehydro-B=0.006%, cortisol=0.016% and DOC=0.04%) and minimum detection limit for DOC ELISA was 2.2 pg/mL (6.6 pmol/L), and for B ELISA was 6.2 pg/mL (17.9 pmol/L). The validity of urinary DOC and B ELISAs was confirmed by the excellent correlation between the results obtained before and after solvent extraction and HPLC (DOC ELISA: Y=1.092X-0.054, R(2)=0.988; B ELISA: Y=1.047X-0.226, R(2)=0.996). Accuracy studies, parallelism and imprecision data were determined and all found to be satisfactory. The methods were used in a series of metabolic cage studies which demonstrated that (i) females produce more DOC and corticosterone than males; (ii) DOC and corticosterone respond to ACTH treatment but not dietary sodium restriction; (iii) DOC:B ratios in Cyp11b1 null mice were >200-fold greater than wild type.Steroids 08/2009; 74(12):938-44. · 2.83 Impact Factor -
Article: Mineralocorticoid and glucocorticoid receptors stimulate epithelial sodium channel activity in a mouse model of Cushing syndrome.
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ABSTRACT: Experiments in Cushing patients and healthy control subjects receiving adrenocorticotropic hormone (ACTH) indicate that transient renal sodium retention may contribute to the generation of hypertension. Here we have investigated the effect of chronic ACTH infusion on renal sodium handling in adult male C57BL/6J mice using selective antagonists to dissect mineralocorticoid and glucocorticoid receptor-mediated pathways. Mice were infused via osmotic minipump with ACTH (2.5 microg/d) or saline for 2 weeks before being anesthetized for renal function experiments. ACTH caused an increase in blood pressure and a reduction in fractional sodium excretion associated with enhanced activity of the epithelial sodium channel. Given separately, spironolactone and RU38486 blunted the pressor response to ACTH and the increased epithelial sodium channel activity; combined mineralocorticoid and glucocorticoid receptor blockade was required to resolve the response to ACTH excess. Dietary sodium depletion also prevented ACTH-induced hypertension. The effect of increased sodium reabsorption in the distal nephron is offset by downregulation of Na-K-Cl cotransport in the loop of Henle. Sodium excretion is normalized chronically, but blood pressure remains high; acute blockade of V1 receptors and alpha1 adrenoceptors in combination restored blood pressure to control values. In summary, ACTH excess promotes renal sodium reabsorption, contributing to the increased blood pressure; both glucocorticoid and mineralocorticoid receptor pathways are involved. These data are relevant to conditions associated with overactivity of the hypothalamic-pituitary-adrenal axis, such as obesity and chronic stress.Hypertension 08/2009; 54(4):890-6. · 6.21 Impact Factor -
Article: Angiotensin-converting enzyme is a modifier of hypertensive end organ damage.
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ABSTRACT: Severe forms of hypertension are characterized by high blood pressure combined with end organ damage. Through the development and refinement of a transgenic rat model of malignant hypertension incorporating the mouse renin gene, we previously identified a quantitative trait locus on chromosome 10, which affects malignant hypertension severity and morbidity. We next generated an inducible malignant hypertensive model where the timing, severity, and duration of hypertension was placed under the control of the researcher, allowing development of and recovery from end organ damage to be investigated. We have now generated novel consomic Lewis and Fischer rat strains with inducible hypertension and additional strains that are reciprocally congenic for the refined chromosome 10 quantitative trait locus. We have captured a modifier of end organ damage within the congenic region and, using a range of bioinformatic, biochemical and molecular biological techniques, have identified angiotensin-converting enzyme as the modifier of hypertension-induced tissue microvascular injury. Reciprocal differences between angiotensin-converting enzyme and the anti-inflammatory tetrapeptide, N-acetyl-Ser-Asp-Lys-Pro in the kidney, a tissue susceptible to end organ damage, suggest a mechanism for the amelioration of hypertension-dependent damage.Journal of Biological Chemistry 04/2009; 284(23):15564-72. · 4.77 Impact Factor -
Article: Cyp11b1 null mouse, a model of congenital adrenal hyperplasia.
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ABSTRACT: Patients with congenital adrenal hyperplasia arising from mutations of 11beta-hydroxylase, the final enzyme in the glucocorticoid biosynthetic pathway, exhibit glucocorticoid deficiency, adrenal hyperplasia driven by unsuppressed hypothalamo-pituitary-adrenal activity, and excess mineralocorticoid activity caused by the accumulation of deoxycorticosterone. A mouse model, in which exons 3-7 of Cyp11b1 (the gene encoding 11beta-hydroxylase) were replaced with cDNA encoding enhanced cyan fluorescent protein, was generated to investigate the underlying disease mechanisms. Enhanced cyan fluorescent protein was expressed appropriately in the zona fasciculata of the adrenal gland, and targeted knock-out was confirmed by urinary steroid profiles and, immunocytochemically, by the absence of 11beta-hydroxylase. The null mice exhibited glucocorticoid deficiency, mineralocorticoid excess, adrenal hyperplasia, mild hypertension, and hypokalemia. They also displayed glucose intolerance. Because rodents do not synthesize adrenal androgens, changes in reproductive function such as genital virilization of females were not anticipated. However, adult homozygote females were infertile, their ovaries showing an absence of corpora lutea and a central proliferation of disorganized steroidogenic tissue. Null females responded normally to superovulation, suggesting that raised systemic progesterone levels also contribute to infertility problems. The model reveals previously unrecognized phenotypic subtleties of congenital adrenal hyperplasia.Journal of Biological Chemistry 12/2008; 284(6):3925-34. · 4.77 Impact Factor -
Article: Divergent physical activity and novel alternative responses to high fat feeding in polygenic fat and lean mice.
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ABSTRACT: We determined whether altered physical activity levels might underlie the contrasting adiposity of a divergently selected polygenic murine model of metabolic syndrome (Fat; F) and leanness (Lean; L) mice. We measured physical activity with a long term running wheel experiment and performed an additional high fat diet intervention. Further, we measured posture allocation by visual monitoring within the home cage as a non-exercise correlate of 'normal' physical activity. Whilst initially similar, running wheel activity of the F line declined with age, while the activity of the L line increased. Food intake was higher in the L line and increased with wheel exposure. Vertical rearing measured by video quantification in the home cage, without the stimulus of a running wheel was also significantly higher in the L line. The two lines developed novel alternate strategies to defend their body weight when exposed to high fat diets with a running wheel. F mice increased their running wheel activity, and despite unaltered food intake, still gained weight. L mice reduced their food intake and maintained activity levels without a significant change in body weight. Phenotypic selection for divergence in body fat content has co-segregated with a genetic predisposition for divergent physical activity levels and different strategies for coping with exposure to high fat diets that will facilitate the discovery of the genes underlying these important obesity related traits.Behavior Genetics 06/2008; 38(3):292-300. · 2.52 Impact Factor -
Article: Effects of ACTH, dexamethasone, and adrenalectomy on 11beta-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) gene expression in the rat central nervous system.
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ABSTRACT: Using a highly sensitive quantitative RT-PCR method for the measurement of CYP11B1 (11beta-hydroxylase) and CYP11B2 (aldosterone synthase) mRNAs, we previously demonstrated that CYP11B2 expression in the central nervous system (CNS) is subject to regulation by dietary sodium. We have now quantified the expression of these genes in the CNS of male Wistar Kyoto (WKY) rats in response to systemic ACTH infusion, dexamethasone infusion, and to adrenalectomy. CYP11B1 and CYP11B2 mRNA levels were measured in total RNA isolated from the adrenal gland and discrete brain regions using real-time quantitative RT-PCR. ACTH infusion (40 ng/day for 7 days, N=8) significantly increased CYP11B1 mRNA in the adrenal gland, hypothalamus, and cerebral cortex compared with animals infused with vehicle only. ACTH infusion decreased adrenal CYP11B2 expression but increased expression in all of the CNS regions except the cortex. Dexamethasone (10 microg/day for 7 days, N=8) reduced adrenal CYP11B1 mRNA compared with control animals but had no significant effect on either gene's expression in the CNS. Adrenalectomy (N=6 per group) significantly increased CYP11B1 expression in the hippocampus and hypothalamus and raised CYP11B2 expression in the cerebellum relative to sham-operated animals. This study confirms the transcription of CYP11B1 and CYP11B2 throughout the CNS and demonstrates that gene transcription is subject to differential regulation by ACTH and circulating corticosteroid levels.Journal of Endocrinology 03/2008; 196(2):305-11. · 3.55 Impact Factor -
Article: Prenatal dexamethasone 'programmes' hypotension, but stress-induced hypertension in adult offspring.
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ABSTRACT: Low birth weight in humans is predictive of hypertension in adult life. Although the mechanisms underlying this link remain unknown, fetal overexposure to glucocorticoids has been implicated. We previously showed that prenatal dexamethasone (DEX) exposure in the rat lowers birth weight and programmes adult hypertension. The current study aimed to further investigate the nature of this hypertension and to elucidate its origins. Unlike previous studies, we assessed offspring blood pressure (BP) with radiotelemetry, which is unaffected by stress artefacts of measurement. We show that prenatal DEX during the last week of pregnancy results in offspring of low birth weight (14% reduction) that have lower basal BP in adulthood ( approximately 4-8 mmHg lower); with the commonly expected hypertensive phenotype only being noted when these offspring are subjected to even mild disturbance or a more severe stressor (up to 30 mmHg higher than controls). Moreover, DEX-treated offspring sustain their stress-induced hypertension for longer. Promotion of systemic catecholamine release (amphetamine) induced a significantly greater rise of BP in the DEX animals (77% increase) over that observed in the vehicle controls. Additionally, we demonstrate that the isolated mesenteric vasculature of DEX-treated offspring display greater sensitivity to noradrenaline and other vasoconstrictors. We therefore conclude that altered sympathetic responses mediate the stress-induced hypertension associated with prenatal DEX programming.Journal of Endocrinology 03/2008; 196(2):343-52. · 3.55 Impact Factor -
Article: Peripheral mechanisms contributing to the glucocorticoid hypersensitivity in proopiomelanocortin null mice treated with corticosterone.
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ABSTRACT: Proopiomelanocortin (POMC) deficiency causes severe obesity through hyperphagia of hypothalamic origin. However, low glucocorticoid levels caused by adrenal insufficiency mitigate against insulin resistance, hyperphagia and fat accretion in Pomc-/- mice. Upon exogenous glucocorticoid replacement, corticosterone-supplemented (CORT) Pomc-/- mice show exaggerated responses, including excessive fat accumulation, hyperleptinaemia and insulin resistance. To investigate the peripheral mechanisms underlying this glucocorticoid hypersensitivity, we examined the expression levels of key determinants and targets of glucocorticoid action in adipose tissue and liver. Despite lower basal expression of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), which generates active glucocorticoids within cells, CORT-mediated induction of 11beta-HSD1 mRNA levels was more pronounced in adipose tissues of Pomc-/- mice. Similarly, CORT treatment increased lipoprotein lipase mRNA levels in all fat depots in Pomc-/- mice, consistent with exaggerated fat accumulation. Glucocorticoid receptor (GR) mRNA levels were selectively elevated in liver and retroperitoneal fat of Pomc-/- mice but were corrected by CORT in the latter depot. In liver, CORT increased phosphoenolpyruvate carboxykinase mRNA levels specifically in Pomc-/- mice, consistent with their insulin-resistant phenotype. Furthermore, CORT induced hypertension in Pomc-/- mice, independently of adipose or liver renin-angiotensin system activation. These data suggest that CORT-inducible 11beta-HSD1 expression in fat contributes to the adverse cardiometabolic effects of CORT in POMC deficiency, whereas higher GR levels may be more important in liver.Journal of Endocrinology 08/2007; 194(1):161-70. · 3.55 Impact Factor -
Article: Forebrain mineralocorticoid receptor overexpression enhances memory, reduces anxiety and attenuates neuronal loss in cerebral ischaemia.
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ABSTRACT: The nuclear mineralocorticoid receptor (MR), a high-affinity receptor for glucocorticoids, is highly expressed in the hippocampus where it underpins cognitive, behavioural and neuroendocrine regulation. Increased neuronal MR expression occurs early in the response to cellular injury in vivo and in vitro and is associated with enhanced neuronal survival. To determine whether increased neuronal MR might be causal in protecting against ischaemic damage in vivo we generated a forebrain-specific MR-overexpressing transgenic mouse (MR-Tg) under the control of the CamKII alpha promoter, and subjected mice to transient cerebral global ischaemia induced by bilateral common carotid artery occlusion for 20 min. We also separately assessed the effects of MR overexpression on hypothalamic-pituitary-adrenal (HPA) axis activity and cognitive and affective functions in noninjured animals. Our results showed that MR-Tg mice had significantly reduced neuronal death following transient cerebral global ischaemia compared to wild-type littermates. This effect was not associated with alterations in basal or poststress HPA axis function or in arterial blood pressure. MR-Tg mice also demonstrated improved spatial memory retention, reduced anxiety and altered behavioural response to novelty. The induction of neuronal MR appears to offer a protective response which has potential therapeutic implications in cerebral ischaemia and cognitive and affective disorders.European Journal of Neuroscience 04/2007; 25(6):1832-42. · 3.63 Impact Factor -
Article: Liver-selective transgene rescue of hypothalamic-pituitary-adrenal axis dysfunction in 11beta-hydroxysteroid dehydrogenase type 1-deficient mice.
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ABSTRACT: 11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD1) acts as a reductase in vivo, regenerating active glucocorticoids within cells from circulating inert 11-keto forms, thus amplifying local glucocorticoid action. 11beta-HSD1 is predominantly expressed in liver and also adipose tissue and brain. Mice deficient in 11beta-HSD1 (11beta-HSD1(-/-)) exhibit adrenal hyperplasia, raised basal corticosterone levels, and increased hypothalamic-pituitary-adrenal (HPA) axis responses to stress. Whereas reduced peripheral glucocorticoid regeneration may explain adrenal hypertrophy and exaggerated stress responses, elevated basal glucocorticoid levels support a role for 11beta-HSD1 within the brain in amplifying glucocorticoid feedback. To test this hypothesis, apolipoprotein E-HSD1 mice overexpressing 11beta-HSD1 in liver were intercrossed with 11beta-HSD1(-/-) mice to determine whether complementation of hepatic 11beta-HSD1 can restore adrenal and HPA defects. Transgene-mediated delivery of 11beta-HSD1 activity to the liver rescued adrenal hyperplasia and reversed exaggerated HPA stress responses in 11beta-HSD1(-/-) mice. Unexpectedly, elevated nadir plasma corticosterone levels were also restored to control levels. Consistent with this, CYP11B1 mRNA expression in the adrenal cortex of 11beta-HSD1(-/-) mice was increased by 50% but returned to control levels in 11beta-HSD1(-/-) mice bearing the apolipoprotein E-HSD1 transgene. 11beta-HSD1(-/-) mice have lower plasma glucose levels, but the fall in plasma corticosterone with sucrose supplementation was similar in 11beta-HSD1(-/-) and control mice, suggesting glucose deficiency is not the main mechanism whereby basal corticosterone levels are elevated in the null mice. Thus, regeneration of glucocorticoids by 11beta-HSD1 in the liver normalizes all aspects of HPA axis dysregulation in 11beta-HSD1(-/-) mice, without restoration of enzyme activity in key feedback areas of the forebrain. Therefore, hepatic glucocorticoid metabolism influences basal as well as stress-associated functions of the HPA axis.Endocrinology 04/2007; 148(3):961-6. · 4.46 Impact Factor -
Article: A polygenic model of the metabolic syndrome with reduced circulating and intra-adipose glucocorticoid action.
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ABSTRACT: Despite major advances in understanding monogenic causes of morbid obesity, the complex genetic and environmental etiology of idiopathic metabolic syndrome remains poorly understood. One hypothesis suggests that similarities between the metabolic disease of plasma glucocorticoid excess (Cushing's syndrome) and idiopathic metabolic syndrome results from increased glucocorticoid reamplification within adipose tissue by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD-1). Indeed, 11beta-HSD-1 is now a major therapeutic target. Because much supporting evidence for a role of adipose 11beta-HSD-1 comes from transgenic or obese rodents with single-gene mutations, we investigated whether the predicted traits of metabolic syndrome and glucocorticoid metabolism were coassociated in a unique polygenic model of obesity developed by long-term selection for divergent fat mass (Fat and Lean mice with 23 vs. 4% fat as body weight, respectively). Fat mice exhibited an insulin-resistant metabolic syndrome including fatty liver and hypertension. Unexpectedly, Fat mice had a marked intra-adipose (11beta-HSD-1) and plasma glucocorticoid deficiency but higher liver glucocorticoid action. Furthermore, metabolic disease was exacerbated only in Fat mice when challenged with exogenous glucocorticoids or a high-fat diet. Our data suggest that idiopathic metabolic syndrome might associate with such a novel pattern of glucocorticoid action and sensitivity in humans, with implications for tissue-specific therapeutic targeting of 11beta-HSD-1.Diabetes 01/2006; 54(12):3371-8. · 8.29 Impact Factor -
Article: Preventing local regeneration of glucocorticoids by 11beta-hydroxysteroid dehydrogenase type 1 enhances angiogenesis.
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ABSTRACT: Angiogenesis restores blood flow to healing tissues, a process that is inhibited by high doses of glucocorticoids. However, the role of endogenous glucocorticoids and the potential for antiglucocorticoid therapy to enhance angiogenesis is unknown. Using in vitro and in vivo models of angiogenesis in mice, we examined effects of (i) endogenous glucocorticoids, (ii) blocking endogenous glucocorticoid action with the glucocorticoid receptor antagonist RU38486, and (iii) abolishing local regeneration of glucocorticoids by the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1). Glucocorticoids, administered at physiological concentrations, inhibited angiogenesis in an in vitro aortic ring model and in vivo in polyurethane sponges implanted s.c. RU38486-enhanced angiogenesis in s.c. sponges, in healing surgical wounds, and in the myocardium of mice 7 days after myocardial infarction induced by coronary artery ligation. 11betaHSD1 knockout mice showed enhanced angiogenesis in vitro and in vivo within sponges, wounds, and infarcted myocardium. Endogenous glucocorticoids, including those generated locally by 11betaHSD1, exert tonic inhibition of angiogenesis. Inhibition of 11betaHSD1 in liver and adipose has been advocated to reduce cardiovascular risk in the metabolic syndrome: these data suggest that 11betaHSD1 inhibition offers a previously uncharacterized therapeutic approach to improve healing of ischemic or injured tissue.Proceedings of the National Academy of Sciences 09/2005; 102(34):12165-70. · 9.68 Impact Factor
Top co-authors
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Institutions
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2003–2012
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The University of Edinburgh
- • Centre for Cardiovascular Science
- • Centre for Molecular Medicine
Edinburgh, SCT, United Kingdom
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2009
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Queen Margaret University
Edinburgh, SCT, United Kingdom
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