Stimulus-selective induction of the orphan nuclear receptor NGFIB underlies different influences of angiotensin II and potassium on the human adrenal gland zona glomerulosa-specific 3&amp;beta;-HSD isoform gene expression in adrenocortical H295R cells

Yarimizu, Daisuke; Doi, Masao; Ota, Takumi; Okamura, Hitoshi

doi:10.1507/endocrj.ej15-0211

Cited by 8 publications

(4 citation statements)

References 23 publications

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“…Given the findings that an adenylyl cyclase inhibitor and a PKA inhibitor abolished the enhanced cortisol secretion by orexin A [ 37 ], the cAMP/PKA pathway is possibly linked to the roles of orexin A in adrenocortical steroidogenesis. Moreover, it has been recently demonstrated that HSD3B1 is expressed in the zone glomerulosa and is stimulated by Ang II rather than potassium [ 38 , 39 ].…”

Section: Resultsmentioning

confidence: 99%

Interaction of Orexin and Bone Morphogenetic Proteins in Steroidogenesis by Human Adrenocortical Cells

Soejima

Iwata

Nishioka

et al. 2023

IJMS

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Orexins are neuropeptides that play important roles in sleep-wake regulation and food intake in the central nervous system, but their receptors are also expressed in peripheral tissues, including the endocrine system. In the present study, we investigated the functions of orexin in adrenal steroidogenesis using human adrenocortical H295R cells by focusing on its interaction with adrenocortical bone morphogenetic proteins (BMPs) that induce adrenocortical steroidogenesis. Treatment with orexin A increased the mRNA levels of steroidogenic enzymes including StAR, CYP11B2, CYP17, and HSD3B1, and these effects of orexin A were further enhanced in the presence of forskolin. Interestingly, orexin A treatment suppressed the BMP-receptor signaling detected by Smad1/5/9 phosphorylation and Id-1 expression through upregulation of inhibitory Smad7. Orexin A also suppressed endogenous BMP-6 expression but increased the expression of the type-II receptor of ActRII in H295R cells. Moreover, treatment with BMP-6 downregulated the mRNA level of OX1R, but not that of OX2R, expressed in H295R cells. In conclusion, the results indicate that both orexin and BMP-6 accelerate adrenocortical steroidogenesis in human adrenocortical cells; both pathways mutually inhibit each other, thereby leading to a fine-tuning of adrenocortical steroidogenesis.

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Section: Resultsmentioning

confidence: 99%

Interaction of Orexin and Bone Morphogenetic Proteins in Steroidogenesis by Human Adrenocortical Cells

Soejima

Iwata

Nishioka

et al. 2023

IJMS

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“…This suggests that ACAT1 is associated with suppressed CYP11B2 expression via repression of NURR1 and NGFIB. NURR1 primarily regulates CYP11B2 expression, while NGFIB regulates the expression of other steroidogenic genes [ 21 , 23 , 24 ]. Therefore, it is hypothesized that YM750 selectively suppresses NURR1 expression as compared to NGFIB expression, thereby suppressing CYP11B2 expression specifically.…”

Section: Discussionmentioning

confidence: 99%

YM750, an ACAT Inhibitor, Acts on Adrenocortical Cells to Inhibit Aldosterone Secretion Due to Depolarization

Shimada

Hata

Yamazaki

et al. 2022

IJMS

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Primary aldosteronism (PA) is considered the most common form of secondary hypertension, which is associated with excessive aldosterone secretion in the adrenal cortex. The cause of excessive aldosterone secretion is the induction of aldosterone synthase gene (CYP11B2) expression by depolarization of adrenocortical cells. In this study, we found that YM750, an Acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitor, acts on adrenocortical cells to suppress CYP11B2 gene expression and aldosterone secretion. YM750 inhibited the induction of CYP11B2 gene expression by KCl stimulation, but not by angiotensin II and forskolin stimulation. Interestingly, YM750 did not inhibit KCl-stimulated depolarization via an increase in intracellular calcium ion concentration. Moreover, ACAT1 expression was relatively abundant in the zona glomerulosa (ZG) including these CYP11B2-positive cells. Thus, YM750 suppresses CYP11B2 gene expression by suppressing intracellular signaling activated by depolarization. In addition, ACAT1 was suggested to play an important role in steroidogenesis in the ZG. YM750 suppresses CYP11B2 gene expression and aldosterone secretion in the adrenal cortex, suggesting that it may be a potential therapeutic agent for PA.

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“…Romero et al (2007) demonstrated by in vitro study that NGFIB, NURR1, and NOR1 upregulated the expression of CYP11B2. Recently, Yarimizu et al (2015) reported that in response to both angiotensin II and K + , the phosphorylation of the CREB/ATF family transcription factor ATF2 occurs, and it binds to the CYP11B2 promoter and activates the transcription. Subsequently, Hattangady et al (2016) have demonstrated the mutation of KCNJ5 also causes the activation of CYP11B2 transcriptional regulators, NURR1 and ATF2.…”

Section: Transcription Factors Of Cyp11b2 In Apamentioning

confidence: 99%

Expression of CYP11B2 in Aldosterone-Producing Adrenocortical Adenoma: Regulatory Mechanisms and Clinical Significance

Nakamura

Yamazaki

Tezuka

et al. 2016

Tohoku J. Exp. Med.

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Aldosterone-producing adrenocortical adenoma (APA) is responsible for the majority of cases clinically diagnosed as primary aldosteronism. Aldosterone synthase (CYP11B2) is one of the enzymes that play essential roles in aldosterone synthesis and is involved in the pathogenesis of APA. Recent studies have demonstrated that various factors and regulators influence the expression and function of CYP11B2 in APA. In particular, somatic mutations, such as gain-of-function and loss-of-function mutations, have been identified in several genes, each of which encodes a pivotal protein that affects the calcium signaling pathway, the expression of CYP11B2, and aldosterone production. The gain-of-function mutations were reported in KCNJ5 that encodes G-protein activated inward rectifier K + channel 4 (Kir3.4) and in CACNA1D, encoding calcium channel, voltage-dependent, L type, alpha subunit Cav1.3. The loss-of-function mutations were found in ATP1A1 that encodes Na + /K + ATPase α subunit and in ATP2B3, encoding Ca 2+ ATPase. Furthermore, the aberrant expression of gonadotropin-releasing hormone receptor is associated with the overexpression of CYP11B2 and overproduction of aldosterone in APA with activating mutations in CTNNB1 encoding β-catenin. On the other hand, CYP11B2 also catalyzes the conversion of cortisol to 18-hydroxycortisol and subsequently converts 18-hydroxycortisol to 18-oxocortisol. The recent studies have identified 18-oxocortisol as an important and distinct biomarker to diagnose primary aldosteronism. In this review, we summarize the recent findings on CYP11B2 and discuss the molecular pathogenesis of APA and the clinical significance of CYP11B2.

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Stimulus-selective induction of the orphan nuclear receptor NGFIB underlies different influences of angiotensin II and potassium on the human adrenal gland zona glomerulosa-specific 3β-HSD isoform gene expression in adrenocortical H295R cells

Cited by 8 publications

References 23 publications

Interaction of Orexin and Bone Morphogenetic Proteins in Steroidogenesis by Human Adrenocortical Cells

Interaction of Orexin and Bone Morphogenetic Proteins in Steroidogenesis by Human Adrenocortical Cells

YM750, an ACAT Inhibitor, Acts on Adrenocortical Cells to Inhibit Aldosterone Secretion Due to Depolarization

Expression of CYP11B2 in Aldosterone-Producing Adrenocortical Adenoma: Regulatory Mechanisms and Clinical Significance

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