Is the Mineralocorticoid Receptor in Brown Norway Rats Constitutively Active?

Marissal-Arvy, Nathalie; Ribot, Emeline J.; Sarrieau, Alain; Mormède, Pierre

doi:10.1046/j.1365-2826.2000.00502.x

Cited by 9 publications

(20 citation statements)

References 70 publications

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“…A treatment with DOC had no effect in BN rats, whereas it restored saline intake of the F344 ADX rats to control levels (15). Alternatively, a treatment with the GR-specific agonist RU28362 induced greater weight loss, thymus involution, and decrease in food intake and plasma transcortin concentration in BN than in F344 rats, suggesting a greater efficiency of GR activity in BN rats (15). This apparent insensitivity to ADX and the greater GR efficiency of the BN rat were observed in F1 hybrid F344xBN rats, indicating dominance of the BN allele(s) on these traits (16).…”

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confidence: 86%

“…F2 BNxF344 rats (n ϭ 227) were submitted at 6 -7 weeks of age to the phenotypic measurements previously described as the most discriminant between BN and F344 inbred strains (15): weight loss, food and saline intake in response to ADX or to treatments with MR or GR-specific ligands (DOC or RU28362, respectively) after ADX, and adrenal weight. Bilateral ADX was performed after a control period of 6 days.…”

Section: Phenotyping Of the F2 Bnxf344 Populationmentioning

confidence: 99%

“…The F2 rats were submitted to the phenotypic measurements the most discriminant between BN and F344 strains (15). At first, the BsaMI restriction site was used to distinguish the BN and F344 MR alleles in the F2 population.…”

Section: F2 Rats Bearing the Bn Mr Locus Are Partly Protected Againstmentioning

confidence: 99%

“…ADX did not alter saline and food intake and induced only very transient effects on the Na ϩ /K ϩ excretions, suggesting a ligand-independent MR activation in BN rat. A treatment with DOC had no effect in BN rats, whereas it restored saline intake of the F344 ADX rats to control levels (15). Alternatively, a treatment with the GR-specific agonist RU28362 induced greater weight loss, thymus involution, and decrease in food intake and plasma transcortin concentration in BN than in F344 rats, suggesting a greater efficiency of GR activity in BN rats (15).…”

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confidence: 96%

“…To unravel the network of interactions between the components of the hypothalamic-pituitary-adrenal axis, BN and F344 rats were treated with adrenalectomy (ADX) to remove the feedback regulation exerted by corticosteroids (14,15). As classically described, ADX induced weight loss and markedly increased saline intake in F344 rats.…”

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confidence: 99%

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Gain of Function Mutation in the Mineralocorticoid Receptor of the Brown Norway Rat

Marissal-Arvy

Lombès

Petterson

et al. 2004

Journal of Biological Chemistry

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The aim of this research was to identify the molecular bases of differences in sensitivity to corticosteroid hormones between Brown Norway and Fischer 344 rats. We previously showed an apparent insensitivity to adrenalectomy in Brown Norway rats. Based on our first hypothesis of a different activity/reactivity of the mineralocorticoid signaling pathway between the two rat strains, we sequenced Brown Norway and Fischer 344 mineralocorticoid receptor cDNA and identified a tyrosine to cysteine substitution (Y73C) in the N-terminal part of the Brown Norway mineralocorticoid receptor. As a first step, this substitution gave us a means to distinguish the Brown Norway allele from the Fischer 344 at the mineralocorticoid receptor locus in an F2 population. We showed a strong genetic linkage between the mineralocorticoid receptor genotype and sensitivity to adrenalectomy. A subsequent genome-wide linkage analysis confirmed the involvement of the mineralocorticoid receptor locus and implicated other loci, including one on chromosome 4, which collectively explain a large part of the strain differences in corticosteroid receptor responses. In vitro studies further revealed that the Y73C substitution induces greater transactivation of the mineralocorticoid receptor by aldosterone, and surprisingly by progesterone as well, which could substitute for aldosterone after adrenalectomy in Brown Norway rats. We challenged this hypothesis in vivo and showed that plasma progesterone is higher in Brown Norway male rats and partially compensates for aldosterone after adrenalectomy. This work illustrates the interest of a pluristrategic approach to explore the mineralocorticoid receptor signaling pathway and its implication in the regulation of hydroelectrolytic homeostasis and blood pressure.Adrenal steroids act through two receptor subtypes: the mineralocorticoid receptor (MR), 1 which exhibits a high affinity for aldosterone, deoxycorticosterone (DOC), and endogenous glucocorticoids (K d ϭ 0.5-1.0 nM), and the glucocorticoid receptor (GR), which binds cortisol and corticosterone with a lower affinity (K d ϭ 2.5-5.0 nM) than synthetic agonists like dexamethasone or RU28362 (K d ϭ 0.5-1.0 nM). Like other nuclear receptors, MR and GR bind to cis-acting DNA elements in the regulatory regions of target genes (1). The MR is located predominately in sodium-transporting epithelia and in the limbic system. It is involved in the maintenance of blood pressure (2) and brain function (3). The GR has a widespread distribution and is involved in almost all organic functions, including carbohydrate and lipid metabolism, modulation of immune responses, and behavior (4 -6). Both receptor types are also involved in the control of hypothalamic-pituitary-adrenal axis activity and reactivity to stress (7). Numerous diseases, such as hypertension, autoimmunity, obesity, mood, and behavioral disorders, are associated with disturbed corticosteroid secretion or action (8 -10). Vulnerability to such dysfunctions shows high interindividual variation, and the in...

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mentioning

confidence: 86%

Section: Phenotyping Of the F2 Bnxf344 Populationmentioning

confidence: 99%

Section: F2 Rats Bearing the Bn Mr Locus Are Partly Protected Againstmentioning

confidence: 99%

mentioning

confidence: 96%

mentioning

confidence: 99%

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Gain of Function Mutation in the Mineralocorticoid Receptor of the Brown Norway Rat

Marissal-Arvy

Lombès

Petterson

et al. 2004

Journal of Biological Chemistry

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Testosterone, Corticosterone, and Photoperiod Interact to Regulate Plasma Levels of Binding Globulin and Free Steroid Hormone in Dark-Eyed Juncos, Junco hyemalis

Deviche

Breuner

Orchinik

2001

General and Comparative Endocrinology

132

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QTL mapping for traits associated with stress neuroendocrine reactivity in rats

et al. 2005

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In the present study we searched for quantitative trait loci (QTLs) that affect neuroendocrine stress responses in a 20-min restraint stress paradigm using Brown-Norway (BN) and Wistar-Kyoto-Hyperactive (WKHA) rats. These strains differed in their hypothalamic-pituitary-adrenal axis (plasma ACTH and corticosterone levels, thymus, and adrenal weights) and in their renin-angiotensin-aldosterone system reactivity (plasma renin activity, aldosterone concentration). We performed a whole-genome scan on a F2 progeny derived from a WKHA x BN intercross, which led to the identification of several QTLs linked to plasma renin activity (Sr6, Sr8, Sr11, and Sr12 on chromosomes RNO2, 3, 19, and 8, respectively), plasma aldosterone concentration (Sr7 and Sr9 on RNO2 and 5, respectively), and thymus weight (Sr10, Sr13, and Srl4 on RNO5, 10, and 16, respectively). The type 1b angiotensin II receptor gene (Agtrlb) maps within the confidence intervals of QTLs on RNO2 linked to plasma renin activity (Sr6, highly significant; LOD = 5.0) and to plasma aldosterone level (Sr7, suggestive; LOD = 2.0). In vitro studies of angiotensin II-induced release of aldosterone by adrenal glomerulosa cells revealed a lower receptor potency (log EC50 = -8.16 +/- 0.11 M) and efficiency (Emax = 453.3 +/- 25.9 pg/3 x 10(4) cells/24 h) in BN than in WKHA (log EC50 = -10.66 +/- 0.18 M; Emax = 573.1 +/- 15.3 pg/3 x 10(4) cells/24 h). Moreover, differences in Agtr1b mRNA abundance and sequence reinforce the putative role of the Agtr1b gene in the differential plasma renin stress reactivity between the two rat strains.

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Is the Mineralocorticoid Receptor in Brown Norway Rats Constitutively Active?

Cited by 9 publications

References 70 publications

Gain of Function Mutation in the Mineralocorticoid Receptor of the Brown Norway Rat

Gain of Function Mutation in the Mineralocorticoid Receptor of the Brown Norway Rat

Testosterone, Corticosterone, and Photoperiod Interact to Regulate Plasma Levels of Binding Globulin and Free Steroid Hormone in Dark-Eyed Juncos, Junco hyemalis

QTL mapping for traits associated with stress neuroendocrine reactivity in rats

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