Glucocorticoid receptor variants: clinical implications

DeRijk, Roel H.; Schaaf, Marcel J. M.; Kloet, E. Ronald de

doi:10.1016/s0960-0760(02)00062-6

Cited by 226 publications

(163 citation statements)

References 136 publications

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“…[37][38][39] The presence of glucocorticoid-responsive elements in the human AT2R has been reported previously. 40 Alternatively, MRs could indirectly modulate AT2R expression, ie, via activation of activating protein-1 (Fos/Jun).…”

Section: Discussionsupporting

confidence: 52%

High-Salt Diet Inhibits Expression of Angiotensin Type 2 Receptor in Resistance Arteries

et al. 2005

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Abstract-Recent studies suggested that type 2 angiotensin receptor (AT2R) could contribute to regulation of blood pressure and/or vascular remodeling. A key question relates to the effects of potential modulators of vascular AT2R expression. In the present work, we evaluated if high salt intake (70 mmol/L NaCl in drinking water) could modulate rat mesenteric artery AT2R function and expression. Angiotensin II dose-response curves were studied in rat perfused pressurized small-diameter arteries in the presence of losartan (AT1R antagonist Key Words: mineralocorticoid Ⅲ sodium Ⅲ hypertension Ⅲ vascular remodeling Ⅲ apoptosis T he renin-angiotensin-aldosterone system (RAAS) regulates vascular tone, body fluid volume, electrolyte balance, hormonal secretion, and neuronal activity. The biological effects of angiotensin II (Ang II), the main effector peptide in the vasculature, are mediated by at least 2 receptor isofoms. 1,2 The type 1 receptor (AT1R) mediates vasoconstriction, sympathetic facilitation, and trophic effects. The type 2 receptor (AT2R) is widely expressed during fetal development, whereas in the adult its expression has been detected in many different vessel types, including mesenteric, coronary, and renal arteries. 3-6 AT2R has opposite effects to those of AT1R, ie, it promotes cell apoptosis and inhibits cell proliferation. 6,7 AT2R also attenuates the pressor action of Ang II 8 and mediates vasodilation. 9,10 Recently, it has been shown that Ang II relaxes small mesenteric arteries via AT2R when AT1R are blocked. [11][12][13] Interestingly, the expression of AT2R is increased in several pathologic conditions such as vascular injury, 14 cardiac remodeling, congestive heart failure, and myocardial infarction. 15,16 It has been suggested that in adults the presence of AT2R in vascular tissues may be playing a role in vascular tone and/or tissue remodeling. [17][18][19] Therefore, a key and complex question that arises is how AT1R and AT2R expression are modulated. Several studies indicate interaction between Ang II and aldosterone, affecting the expression of ATRs. The expression of AT1R appears to be induced by Ang II in vascular smooth muscle, 4 and mineralocorticoids potentiate the action of Ang II in cultured rat vascular smooth muscle cells (VSMCs) by increasing the number of AT1R. 20,21 However, there are few data concerning the physiological regulation of AT2R expression. Dietary sodium depletion, which increases RAAS activity, enhances renal AT2 receptor function 10,22 and expression in both young and mature adult rats, mainly in the glomeruli and interstitial cells. 23 Induction of AT2R-mediated modulation of blood pressure was described in rats fed with a synthetic diet, an effect attributed to the stimulation of the RAAS. 8 Bonnet et al 24 have shown that Ang II infusion in the rat induces the expression of AT2R in the mesenteric vasculature. Nevertheless, it is not clear whether Ang II directly mediates the increased AT2R expression or if it is secondary to direct aldosterone action on arte...

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Section: Discussionsupporting

confidence: 52%

High-Salt Diet Inhibits Expression of Angiotensin Type 2 Receptor in Resistance Arteries

et al. 2005

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“…However, there is considerable individual variation in sensitivity to GCs (Hearing et al 1999), which may affect the outcome of GC treatment. Mutations and splice variation in the GR gene and subsequent polymorphisms in the protein of humans and other vertebrates may explain the individual variation in sensitivity, rather than alteration in the consensus sequence of the GR-binding site in the DNA of target genes (Brandon et al 1991, Keightley & Fuller 1994, Lamberts et al 1996, DeRijk et al 2002, van Rossum et al 2002, Bray & Cotton 2003, Stevens et al 2004b.…”

Section: Introductionmentioning

confidence: 99%

Evolution of glucocorticoid receptors with different glucocorticoid sensitivity

Stolte¹,

Kemenade²,

Savelkoul³

et al. 2006

Journal of Endocrinology

148

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Glucocorticoids (GCs) are commonly used to treat a variety of immune diseases. However, the efficacy of treatment is greatly influenced by an individual variation in sensitivity to GCs, which is caused by differences in the glucocorticoid receptor (GR). The variable receptor profile results from variations in the GR gene, or alternative splicing of the gene coded. We investigated the evolution of the GR gene by comparing genomic GR sequences of vertebrates. Exon length and amino acid sequence are conserved among all classes of vertebrates studied, which indicates strong evolutionary pressure on conservation of this gene. Interestingly, teleostean fishes have two different GR proteins. One of the duplicate fish GR genes has a nine-amino-acid insert in the DNA binding region that results from alternative splicing. The duplicate GR genes and products of alternative splicing in teleostean fishes are differentially expressed in vivo and show different transactivation capacity in vitro. The presence of two GR genes appears to be a result of divergence of receptors rather than of ligands. Teleostean fishes express different, evolutionarily related, functional GR proteins within a single organism. Hereby, teleostean fishes present a model that facilitates investigation of the molecular basis of cortisol resistance and different regulatory functions of cortisol.

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“…15,16 GCCR encodes the glucocorticoid receptor, and glucocorticoids are important regulators of immunity and inflammation. 17 HLA-HB1 encodes minor histocompatibility antigen HB-1 and is predominantly expressed by immunological effector cells. SLC22A4 and SLC22A5 had been reported to be associated with Crohn disease and rheumatoid arthritis, which, similar to GD, had the pathogenesis associated with inflammation and autoimmunity.…”

Section: Introductionmentioning

confidence: 99%

Polymorphisms in the interleukin 3 gene show strong association with susceptibility to Graves’ disease in Chinese population

et al. 2009

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Graves' disease (GD) is a common organ-specific autoimmune disorder, which is multifactorial and develops in genetically susceptible individuals. We had earlier mapped a susceptibility locus for GD to chromosome 5q31-33 in a linkage study. Here we used tag single-nucleotide polymorphisms (SNPs) to search for genetic variants associated with GD, and examined 19 functional candidate genes in this chromosomal region. We identified 192 polymorphisms by re-sequencing the candidate genes, and selected 51 tagSNPs to genotype in a case-control collection of 1118 south Han Chinese subjects (428 cases and 690 controls). Initial analysis suggested that a non-synonymous SNP rs40401 (P27S) of interleukin 3 (IL3) was associated with GD, and further fine-mapping showed that rs40401, or its perfect proxy SNP rs31480 in the 5 0 flanking region of IL3, fully accounted for the association signal at this locus. We replicated significant association of rs40401 with GD in an independent sample collection of 839 north Han Chinese subjects. A combined analysis revealed strong validation of this association (odds ratio (OR common ) ¼ 1.63, combined P (P comb ) ¼ 4 Â 10 À6 in the Recessive disease model). This study provides convincing evidence that the IL3 gene is a susceptibility locus for GD in the Chinese population.

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Glucocorticoid receptor variants: clinical implications

Cited by 226 publications

References 136 publications

High-Salt Diet Inhibits Expression of Angiotensin Type 2 Receptor in Resistance Arteries

High-Salt Diet Inhibits Expression of Angiotensin Type 2 Receptor in Resistance Arteries

Evolution of glucocorticoid receptors with different glucocorticoid sensitivity

Polymorphisms in the interleukin 3 gene show strong association with susceptibility to Graves’ disease in Chinese population

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