Short term regulation of aldosterone secretion after stimulation and suppression experiments in mice

Spyroglou, Ariadni; Manolopoulou, Jenny; Wagner, Sibylle; Bidlingmaier, Martin; Reincke, Martín; Beuschlein, Felix

doi:10.1677/jme-08-0167

Cited by 17 publications

(16 citation statements)

References 34 publications

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“…2C) associated with enhanced activity of the CYP11B2 promoter. The StAR promoter has a binding sequence for CREB/ATF-1 (activating transcription factor-1) that acts synergically with Nurr1 to induce CYP11B2 expression and aldosterone production (Spyroglou et al, 2009). Phosphorylation of CREB was increased in adipocytes stimulated with anacetrapib (Fig.…”

Section: Cetp Inhibitors Stimulate Aldosterone In Adipocytes Resultsmentioning

confidence: 99%

“…Our results show differential regulation of these enzymes by CETP inhibitors. Torcetrapib and dalcetrapib increased expression of Nurr1, a transcription factor that regulates CYP11B2 (Spyroglou et al, 2009), and increased protein content of CYP11B2, whereas anacetrapib increased expression of CREB and StAR. Hence, torcetrapib and dalcetrapib influence pathways associated with chronic aldosterone production, whereas anacetrapib influences processes associated with acute biosynthesis.…”

Section: Discussionmentioning

confidence: 98%

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Cholesteryl Ester-Transfer Protein Inhibitors Stimulate Aldosterone Biosynthesis in Adipocytes through Nox-Dependent Processes

Neves

Cat

Even

et al. 2015

J Pharmacol Exp Ther

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Hyperaldosteronism and hypertension were unexpected side effects observed in trials of torcetrapib, a cholesteryl ester-transfer protein (CETP) inhibitor that increases high-density lipoprotein. Given that CETP inhibitors are lipid soluble, accumulate in adipose tissue, and have binding sites for proteins involved in adipogenesis, and that adipocytes are a source of aldosterone, we questioned whether CETP inhibitors (torcetrapib, dalcetrapib, and anacetrapib) influence aldosterone production by adipocytes. Studies were performed using human adipocytes (SW872), which express CETP, and mouse adipocytes (3T3-L1), which lack the CETP gene. Torcetrapib, dalcetrapib, and anacetrapib increased expression of CYP11B2, CYP11B1, and steroidogenic acute regulatory protein, enzymes involved in mineralocorticoid and glucocorticoid generation. These effects were associated with increased reactive oxygen species formation. Torcetrapib, dalcetrapib, and anacetrapib upregulated signal transducer and activator of transcription 3 (STAT3) and peroxisome proliferation-activated receptor-g, important in adipogenesis, but only torcetrapib stimulated production of chemerin, a proinflammatory adipokine. To determine mechanisms whereby CETP inhibitors mediate effects, cells were pretreated with inhibitors of Nox1/Nox4 [GKT137831; 2-(2-chlorophenyl)-4-[3- sulfonyloxy)acetyl)amino)-benzoic acid]). In torcetrapib-stimulated cells, Nox inhibitors, rotenone, and S3I-201 downregulated CYP11B2 and steroidogenic acute regulatory protein and reduced aldosterone. Dalcetrapib and anacetrapib effects on aldosterone were variably blocked by GKT137831, ML171, rotenone, and S3I-201. In adipocytes, torcetrapib, dalcetrapib, and anacetrapib inhibit enzymatic pathways responsible for aldosterone production through Nox1/Nox4-and mitochondrial-generated reactive oxygen species and STAT3. CETP inhibitors also influence adipokine production. These processes may be CETP independent. Our findings identify novel adipocyte-related mechanisms whereby CETP inhibitors increase aldosterone production. Such phenomena may contribute to hyperaldosteronism observed in CETP inhibitor clinical trials.

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Section: Cetp Inhibitors Stimulate Aldosterone In Adipocytes Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 98%

Cholesteryl Ester-Transfer Protein Inhibitors Stimulate Aldosterone Biosynthesis in Adipocytes through Nox-Dependent Processes

Neves

Cat

Even

et al. 2015

J Pharmacol Exp Ther

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“…These transcription factors in turn activate promoter sites of the CYP11B2 gene and increase transcription of aldosterone synthase (30,41). While these transcriptional-based mechanisms had initially been reported in the context of chronic stimulation experiments in a time frame of hours to days (41,42), we could demonstrate that in vivo adrenal CYP11B2 expression is upregulated even within minutes upon specific stimulation experiments (43). As activation of CaMK-dependent pathways is detectable in Conn's adenomas (44), it is prudent to expect that these pathways also play a pathophysiological role in autonomous aldosterone secretion.…”

Section: Physiology Of Aldosterone Regulationmentioning

confidence: 62%

EJE Prize 2013: Regulation of aldosterone secretion: from physiology to disease

Beuschlein

2013

European Journal of Endocrinology

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Arterial hypertension is a major cardiovascular risk factor that affects between 10 and 40% of the population in industrialized countries. Primary aldosteronism (PA) is the most common form of secondary hypertension with an estimated prevalence of around 10% in referral centers and 4% in a primary care setting. Despite its high prevalence until recently, the underlying genetic and molecular basis of this common disease had remained largely obscure. Over the past decade, a number of insights have been achieved that have relied on in vitro cellular systems, wild-type and genetically modified in vivo models, as well as clinical studies in well-characterized patient populations. This progress has been made possible by a number of independent technical developments including that of specific hormone assays that allow measurement in small sample volumes as well as genetic techniques that enable high-throughput sequencing of a large number of samples. Furthermore, animal models have provided important insights into the physiology of aldosterone regulation that have served as a starting point for investigation of mechanisms involved in autonomous aldosterone secretion. Finally, national and international networks that have built up registries and biobanks have been instrumental in fostering translational research endeavors in PA. Therefore, it is to be expected that in the near future, further pathophysiological mechanisms that result in autonomous aldosterone secretion will be unraveled. European Journal of Endocrinology 168 R85-R93

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“…This transcriptional regulation had initially been described in the context of chronic (hours to days) in vitro stimulation experiments (Denner et al 1996. However, in vivo, adrenal CYP11B2 levels increase even within minutes upon specific stimulation experiments (Spyroglou et al 2009). Both potassium and angiotensin II can act independently and have equivalent effects on transcriptional regulation of CYP11B2.…”

Section: Introductionmentioning

confidence: 86%

Identification of adrenal genes regulated in a potassium-dependent manner

Dierks

Lichtenauer²,

Sackmann³

et al. 2010

Journal of Molecular Endocrinology

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Potassium and angiotensin II are the main stimulators of aldosterone secretion from the adrenal cortex. As potassiuminduced in vivo gene regulation in the adrenal cortex has not been studied in detail, we applied a stepwise screening approach: first, we investigated the effects of chronic potassium substitution in mice. Microarray analysis of adrenal glands revealed a set of genes (set A) that were counter-regulated in a high potassium (HP) and low potassium substitution group, while others (set B) were highly upregulated in the HP intake group. In a second step, time dependency of expression changes of these pre-defined genes was studied following short-term potassium stimulation experiments in vivo. Thirdly, dose dependency of potassium-induced gene regulation was investigated in vitro. Finally, to provide indirect evidence for the potential relevance of the detected changes for autonomous aldosterone secretion, expression analysis of aldosterone-producing adenomas was compared with normal adrenal glands. While most investigated genes were similarly regulated following long-and short-term potassium stimulation in vivo, observed changes were reproducible in NCI h295R adrenocortical cells mostly for the set of genes identified in the HP group (set B) . Similarly, in Conn's adenomas, mostly genes from set B displayed changes in expression pattern in comparison to normal adrenal glands, while genes from set A were mostly unchanged. Thus, while in vivo models can help in identifying genes potentially involved in potassium-dependent aldosterone secretion, these findings also underline the necessity to interpret potassium-induced gene regulation on the basis of the experimental setting.

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Short term regulation of aldosterone secretion after stimulation and suppression experiments in mice

Cited by 17 publications

References 34 publications

Cholesteryl Ester-Transfer Protein Inhibitors Stimulate Aldosterone Biosynthesis in Adipocytes through Nox-Dependent Processes

Cholesteryl Ester-Transfer Protein Inhibitors Stimulate Aldosterone Biosynthesis in Adipocytes through Nox-Dependent Processes

EJE Prize 2013: Regulation of aldosterone secretion: from physiology to disease

Identification of adrenal genes regulated in a potassium-dependent manner

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