Mechanisms of angiotensin II-mediated regulation of aldosterone synthase expression in H295R human adrenocortical and rat adrenal glomerulosa cells

Szekeres, Mária; Turu, Gábor; Orient, Anna; Szalai, Bence; Süpeki, Katinka; Cserző, Miklós; Várnai, Péter; Hunyady, László

doi:10.1016/j.mce.2008.12.015

Cited by 29 publications

(26 citation statements)

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“…It has been demonstrated that the activation of AT1R and its downstream signalling molecules, mainly ERK and/or CAMKII, mediate most of the biological functions of Ang II (Clyne et al 1993, Fern et al 1995, Côté et al 1998, McEwan et al 1999, Aguilar et al 2004, Otis et al 2005, Romero et al 2006, Szekeres et al 2009. In this study, while there was an increase in the abundance of AT1R, there was no difference in the protein abundance of ERK, CAMKII and their phosphorylated forms in the adrenal of the CR and HR lambs.…”

Section: Discussionmentioning

confidence: 47%

“…A range of in vitro and in vivo experiments have shown that Ang II acts on AT1R to stimulate cellular proliferation and hypertrophy in the adrenal and to increase adrenal steroid secretion (Clyne et al 1993, McEwan et al 1999, Aguilar et al 2004, Romero et al 2006. AT1R activation results in the activation/phosphorylation of the MAPK pathways, including MEK-ERK1/2 and calcium/calmodulindependent kinases (Fern et al 1995, Cô té et al 1998, Condon et al 2002, Otis et al 2005, Szekeres et al 2009). …”

Section: Introductionmentioning

confidence: 99%

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Dietary restriction in the periconceptional period in normal-weight or obese ewes results in increased abundance of angiotensin-converting enzyme (ACE) and angiotensin type 1 receptor (AT1R) in the absence of changes in ACE or AT1R methylation in the adrenal of the offspring

et al. 2013

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Exposure to dietary restriction during the periconceptional period in either normal or obese ewes results in increased adrenal growth and a greater cortisol response to stress in the offspring, but the mechanisms that programme these changes are not fully understood. Activation of the angiotensin type 1 receptor (AT1R) has been demonstrated to stimulate adrenal growth and steroidogenesis. We have used an embryo transfer model in the sheep to investigate the effects of exposure to dietary restriction in normal or obese mothers from before and 1 week after conception on the methylation status, expression, abundance and localisation of key components of the renin-angiotensin system (RAS) in the adrenal of post-natal lambs. Maternal dietary restriction in normal or obese ewes during the periconceptional period resulted in an increase in angiotensin-converting enzyme (ACE) and AT1R abundance in the absence of changes in the methylation status or mRNA expression of ACE and AT1R in the adrenal of the offspring. Exposure to maternal obesity alone also resulted in an increase in adrenal AT1R abundance. There was no effect of maternal dietary restriction or obesity on ACE2 and AT2R or on ERK, calcium/calmodulin-dependent kinase II abundance, and their phosphorylated forms in the lamb adrenal. Thus, weight loss around the time of conception, in both normal-weight and obese ewes, results in changes within the intra-adrenal RAS consistent with increased AT1R activation. These changes within the intra-adrenal RAS system may contribute to the greater adrenal stress response following exposure to signals of adversity in the periconceptional period.

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Section: Discussionmentioning

confidence: 47%

Section: Introductionmentioning

confidence: 99%

Dietary restriction in the periconceptional period in normal-weight or obese ewes results in increased abundance of angiotensin-converting enzyme (ACE) and angiotensin type 1 receptor (AT1R) in the absence of changes in ACE or AT1R methylation in the adrenal of the offspring

et al. 2013

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“…We and others have reported that NGFI-B family members are upregulated by ANG II in H295R cells (4,37,43,46,51) and freshly isolated rat or bovine zona glomerulosa adrenal cells (36,45,51). NGFI-B family members have been reported to regulate the expression of several steroidogenic enzymes, including aldosterone synthase, 11␤-hydroxylase, 3␤-hydroxysteroid dehydrogenase, 17␣-hydroxylase, and 21-hydroxylase in the adrenal gland (3,4,15,32,46,56,57).…”

Section: Discussionmentioning

confidence: 94%

Angiotensin II-regulated transcription regulatory genes in adrenal steroidogenesis

Romero¹,

Gómez-Sánchez

2010

Physiological Genomics

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Transcription regulatory genes are crucial modulators of cell physiology and metabolism whose intracellular levels are tightly controlled in response to extracellular stimuli. We previously reported a set of 29 transcription regulatory genes modulated by angiotensin II in H295R human adrenocortical cells and their roles in regulating the expression of the last and unique enzymes of the glucocorticoid and mineralocorticoid biosynthetic pathways, 11β-hydroxylase and aldosterone synthase, respectively, using gene expression reporter assays. To study the effect of this set of transcription regulatory genes on adrenal steroidogenesis, H295R cells were transfected by high-efficiency nucleofection and aldosterone and cortisol were measured in cell culture supernatants under basal and angiotensin II-stimulated conditions. BCL11B, BHLHB2, CITED2, ELL2, HMGA1, MAFF, NFIL3, PER1, SERTAD1, and VDR significantly stimulated aldosterone secretion, while EGR1, FOSB, and ZFP295 decreased aldosterone secretion. BTG2, HMGA1, MITF, NR4A1, and ZFP295 significantly increased cortisol secretion, while BCL11B, NFIL3, PER1, and SIX2 decreased cortisol secretion. We also report the effect of some of these regulators on the expression of endogenous aldosterone synthase and 11β-hydroxylase under basal and angiotensin II-stimulated conditions. In summary, this study reports for the first time the effects of a set of angiotensin II-modulated transcription regulatory genes on aldosterone and cortisol secretion and the expression levels of the last and unique enzymes of the mineralocorticoid and glucocorticoid biosynthetic pathways. Abnormal regulation of mineralocorticoid or glucocorticoid secretion is involved in several pathophysiological conditions. These transcription regulatory genes may be involved in adrenal steroidogenesis pathologies; thus they merit additional study as potential candidates for therapeutic intervention.

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“…There are many studies describing the AngII response of NGFIB, NURR1, and NOR1 in H295R cells (19,39,40), but it remains unexplored whether the corresponding proteins bind to the cognate DNA element in an AngII stimulation-dependent manner. We therefore performed an electrophoretic mobility shift assay (EMSA) to determine whether the AngIIinduced NGFIB family proteins bind to the potential NBRE site of the HSD3B1 promoter (Fig.…”

Section: Resultsmentioning

confidence: 99%

Angiotensin II Triggers Expression of the Adrenal Gland Zona Glomerulosa-Specific 3β-Hydroxysteroid Dehydrogenase Isoenzyme through De Novo Protein Synthesis of the Orphan Nuclear Receptors NGFIB and NURR1

Ota

Doi

Yamazaki

et al. 2014

Molecular and Cellular Biology

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The 3␤-hydroxysteroid dehydrogenase (3␤-HSD) is an enzyme crucial for steroid synthesis. Two different 3␤-HSD isoforms exist in humans. Classically, HSD3B2 was considered the principal isoform present in the adrenal. However, we recently showed that the alternative isoform, HSD3B1, is expressed specifically within the adrenal zona glomerulosa (ZG), where aldosterone is produced, raising the question of why this isozyme needs to be expressed in this cell type. Here we show that in both human and mouse, expression of the ZG isoform 3␤-HSD is rapidly induced upon angiotensin II (AngII) stimulation. AngII is the key peptide hormone regulating the capacity of aldosterone synthesis. Using the human adrenocortical H295R cells as a model system, we show that the ZG isoform HSD3B1 differs from HSD3B2 in the ability to respond to AngII. Mechanistically, the induction of HSD3B1 involves de novo protein synthesis of the nuclear orphan receptors NGFIB and NURR1. The HSD3B1 promoter contains a functional NGFIB/NURR1-responsive element to which these proteins bind in response to AngII. Knockdown of these proteins and overexpression of a dominant negative NGFIB both reduce the AngII responsiveness of HSD3B1. Thus, the AngII-NGFIB/NURR1 pathway controls HSD3B1. Our work reveals HSD3B1 as a new regulatory target of AngII.T he enzyme 3␤-hydroxysteroid dehydrogenase/⌬ 5 -⌬ 4 -isomerase (3␤-HSD) is essential for the biosynthesis of all active steroid hormones, including those secreted from the adrenal gland (1-4). Whereas two distinct 3␤-HSD isoforms (type I 3␤-HSD, which is encoded by HSD3B1, and type II 3␤-HSD, which is encoded by HSD3B2) exist in humans, it has long been thought that type II 3␤-HSD was the only isoform expressed in the human adrenal glands (1). However, this canonical view was recently revised due to the observation that the alternative isoform, HSD3B1, is expressed within zona glomerulosa (ZG) cells (5, 6), where aldosterone is produced. Interestingly, the mouse also has two isoforms in the adrenal: one (Hsd3b1) is ubiquitous in the cortex, but the other (Hsd3b6) is ZG specific (6-9). Thus, in both species, the adrenals possess a ZG-specific isoform, in addition to the ubiquitous one. However, it remains unknown why these different enzymes are expressed simultaneously in ZG cells. Since these isozymes catalyze the same enzymatic reaction, the question remains open why the newly identified ZG-specific isoform needs to be expressed in ZG cells.Angiotensin II (AngII) is the key peptide hormone in the renin-angiotensin-aldosterone system (RAAS). AngII is a potent secretagogue of the mineralocorticoid aldosterone, which is principally synthesized within the adrenal gland ZG cells through a series of enzymatic reactions that involve multiple enzymes, including 3␤-HSDs. The actions of AngII on ZG cells are often divided into two temporally different phases (10-12): (i) an early (within minutes after stimulation) upregulation of aldosterone synthesis through posttranslational activation of steroidogenic acute regulatory...

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Mechanisms of angiotensin II-mediated regulation of aldosterone synthase expression in H295R human adrenocortical and rat adrenal glomerulosa cells

Cited by 29 publications

References 55 publications

Dietary restriction in the periconceptional period in normal-weight or obese ewes results in increased abundance of angiotensin-converting enzyme (ACE) and angiotensin type 1 receptor (AT1R) in the absence of changes in ACE or AT1R methylation in the adrenal of the offspring

Dietary restriction in the periconceptional period in normal-weight or obese ewes results in increased abundance of angiotensin-converting enzyme (ACE) and angiotensin type 1 receptor (AT1R) in the absence of changes in ACE or AT1R methylation in the adrenal of the offspring

Angiotensin II-regulated transcription regulatory genes in adrenal steroidogenesis

Angiotensin II Triggers Expression of the Adrenal Gland Zona Glomerulosa-Specific 3β-Hydroxysteroid Dehydrogenase Isoenzyme through De Novo Protein Synthesis of the Orphan Nuclear Receptors NGFIB and NURR1

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