Aberrant gonadotropin-releasing hormone receptor (GnRHR) expression and its regulation of CYP11B2 expression and aldosterone production in adrenal aldosterone-producing adenoma (APA)

Nakamura, Yasuhiro; Hattangady, Namita G.; Satoh, Fumitoshi; Morimoto, Ryo; Ito-Saito, Takako; Sugawara, Akira; Ohba, Koji; Takahashi, Kazuhiro; Rainey, William E.; Sasano, Hironobu

doi:10.1016/j.mce.2014.01.016

Cited by 16 publications

(11 citation statements)

References 30 publications

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“…In a subset of non-pregnant PA patients from our cohort, the aberrant GnRHR was expressed and several of these patients had increased aldosterone secretion40. The GnRHR staining identified in normal and APA adrenal tissues in this study was consistent with previous reports41. Although there was increased expression of GnRHR and LHCGR in wild-type APA patients and less in KCNJ5 mutation adenoma42, we further showed patients harboring CTNNB1 mutations over-expressed GnRHR and LHCGR compared adenomas with KCNJ5 mutation in both genders.…”

Section: Discussionsupporting

confidence: 90%

The prevalence of CTNNB1 mutations in primary aldosteronism and consequences for clinical outcomes

Wang

Chueh

et al. 2017

Sci Rep

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Constitutive activation of the Wnt pathway/β-catenin signaling may be important in aldosterone-producing adenoma (APA). However, significant gaps remain in our understanding of the prevalence and clinical outcomes after adrenalectomy in APA patients harboring CTNNB1 mutations. The molecular expression of CYP11B2 and gonadal receptors in adenomas were also explored. Adenomas from 219 APA patients (95 men; 44.2%; aged 50.5 ± 11.9 years) showed a high rate of somatic mutations (n = 128, 58.4%). The majority of them harbored KCNJ5 mutations (n = 116, 52.9%); 8 patients (3.7%, 6 women) had CTNNB1 mutations. Patients with APAs harboring CTNNB1 mutations were older and had shorter duration of hypertension. After adrenalectomy, CTNNB1 mutation carriers had a higher possibility (87.5%) of residual hypertension than other APA patients. APAs harboring CTNNB1 mutations have heterogeneous staining of β-catenin and variable expression of gonadal receptors and both CYP11B1 and CYP11B2. This suggests that CTNNB1 mutations may be more related to tumorigenesis rather than excessive aldosterone production.

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Section: Discussionsupporting

confidence: 90%

The prevalence of CTNNB1 mutations in primary aldosteronism and consequences for clinical outcomes

Wang

Chueh

et al. 2017

Sci Rep

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“…We reported the aberrant expression of GnRHR in APA and confirmed by an in vitro model that the chronic activation of GnRHR with GnRH increased CYP11B2 expression and aldosterone production via the calcium signaling pathway (Nakamura et al 2014b). In addition, Kishimoto et al (2016) has recently reported that patients of APA with the higher GnRHR expression showed higher GnRH-stimulated aldosterone response.…”

Section: The Neural Regulators Of Cyp11b2 Expression In Apamentioning

confidence: 57%

“…Recent studies have developed several analytical methods and revealed many novel and key findings regarding the molecular pathogenesis of APA, especially the upregulation system of aldosterone synthase (CYP11B2) expression in APA (Oki et al 2012;Beuschlein et al 2013;Scholl et al 2013;Nakamura et al 2014b;Hattangady et al 2016).…”

Section: Introductionmentioning

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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“…Previous studies have reported somatic CTNNB1 mutations in APA from male patients or non-pregnant females (Scholl et al 2015a, Akerstrom et al 2016, Wu et al 2017. Moreover, although GNRHR and LHCGR overexpression is found in more than 40% of APA (Nakamura et al 2014, Nicolini et al 2014, CTNNB1 mutations are identified only in 5% (Akerstrom et al 2016), with immunohistochemical evidence for β-catenin activation observed in about twothirds of APA . Further studies are necessary to establish the complex mechanisms affected by CTNNB1 mutations in APA.…”

Section: Mutations Affecting β-Catenin Activationmentioning

confidence: 97%

Somatic and inherited mutations in primary aldosteronism

Fernandes-Rosa

Boulkroun

Zennaro

2017

Journal of Molecular Endocrinology

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Primary aldosteronism (PA), the most common form of secondary hypertension, is caused in the majority of cases by unilateral aldosterone-producing adenoma (APA) or bilateral adrenal hyperplasia. Over the past few years, somatic mutations in KCNJ5, CACNA1D, ATP1A1 and ATP2B3 have been proven to be associated with APA development, representing more than 50% of sporadic APA. The identification of these mutations has allowed the development of a model for APA involving modification on the intracellular ionic equilibrium and regulation of cell membrane potential, leading to autonomous aldosterone overproduction. Furthermore, somatic CTNNB1 mutations have also been identified in APA, but the link between these mutations and APA development remains unknown. The sequence of events responsible for APA formation is not completely understood, in particular, whether a single hit or a double hit is responsible for both aldosterone overproduction and cell proliferation. Germline mutations identified in patients with early-onset PA have expanded the classification of familial forms (FH) of PA. The description of germline KCNJ5 and CACNA1H mutations has identified FH-III and FH-IV based on genetic findings; germline CACNA1D mutations have been identified in patients with very early-onset PA and severe neurological abnormalities. This review summarizes current knowledge on the genetic basis of PA, the association of driver gene mutations and clinical findings and in the contribution to patient care, plus the current understanding on the mechanisms of APA development.

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Aberrant gonadotropin-releasing hormone receptor (GnRHR) expression and its regulation of CYP11B2 expression and aldosterone production in adrenal aldosterone-producing adenoma (APA)

Cited by 16 publications

References 30 publications

The prevalence of CTNNB1 mutations in primary aldosteronism and consequences for clinical outcomes

The prevalence of CTNNB1 mutations in primary aldosteronism and consequences for clinical outcomes

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

Somatic and inherited mutations in primary aldosteronism

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