3β-hydroxysteroid dehydrogenase isoforms in human aldosterone-producing adenoma

Konosu-Fukaya, Sachiko; Nakamura, Yasuhiro; Satoh, Fumitoshi; Felizola, Saulo J.A.; Maekawa, Takashi; Ono, Yoshikiyo; Morimoto, Ryo; Ise, Kazue; Takeda, Ken; Katsu, Koshin; Fujishima, Fumiyoshi; Kasajima, Atsuko; Watanabe, Mika; Arai, Yoichi; Gómez-Sánchez, Elise P.; Gómez-Sánchez, Celso E.; Doi, Masao; Okamura, Hitoshi; Sasano, Hironobu

doi:10.1016/j.mce.2014.10.008

Cited by 41 publications

(41 citation statements)

References 34 publications

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“…Doi et al established antibodies specific for the HSD3B isoforms, 1 and 2, and found that HSD3Β1 was confined to the ZG and HSD3Β2 to the zona fasciculata (ZF) in the non-tumoral adrenal cortex, and HSD3Β2 immunoreactivity was more intense in the tumor cells of APAs than that of HSD3Β1 [38]. In addition, Konosu-Fukaya et al recently demonstrated that HSD3B1, despite its lower levels of expression than HSD3B2, correlated with CYP11B2 at both the protein and mRNA levels in APA tissues, suggesting the involvement of the HSDB1 isoform in the production of aldosterone [36]. Furthermore, in the present study, we demonstrated significant KCNJ5 immunoreactivity in the peritumoral adjacent tissues, particularly in the zG (Fig.…”

Section: Discussionmentioning

confidence: 98%

“…Furthermore, Oki et al demonstrated that the expression of the mutant KCNJ5, T158A, induced a significant increase in CYP11B2, resulting in the increased secretion of aldosterone from the adrenal cortical carcinoma cell line, HAC15 [35]. In addition, Konosu-Fukaya et al recently reported that APAs with the KCNJ5 mutation more strongly expressed CYP11B2 mRNA than the wild-type [36].…”

Section: Discussionmentioning

confidence: 99%

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Characteristics of Japanese aldosterone-producing adenomas with KCNJ5 mutations

et al. 2017

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PRIMARY ALDOSTERONISM (PA) has been reported to affect at least 6~10% of patients with essential hypertension [1][2][3][4][5] and is caused mostly by an adrenal adenoma (aldosterone-producing adenoma, APA) or by adrenal hyperplasia (idiopathic hyperaldosteronism, IHA). Although the tumorigenesis of APA remained unclear, somatic mutations of the potassium Characteristics of Japanese aldosterone-producing adenomas with KCNJ5 mutations Abstract. Somatic mutations in KCNJ5 gene have been identified in patients with adrenal aldosterone-producing adenomas (APAs). We previously reported that Japanese patients with APAs had distinct characteristics from patients in Western countries; i.e. they had a high frequency of KCNJ5 mutations and exhibited a frequent association with cortisol cosecretion. Therefore, APAs among Japanese patients may have different features from those in Western countries. We added recent cases, examined 47 cases (43% male) of APAs, including clinicopathological features, KCNJ5 mutations, and the mRNA levels of several steroidogenic enzymes, and compared the results obtained to those reported in other countries. While the prevalence of KCNJ5 mutations is approximately 40% in Western countries, 37 APA cases (78.7%) showed mutations: 26 with p.G151R and 11 with p.L168R. Although a significant gender difference has been reported in the frequency of KCNJ5 mutations in Europe, we did not find any gender difference. However, the phenotypes of Japanese patients with mutations were similar to those of patients in Western countries; patients were younger and had higher plasma aldosterone levels, lower potassium levels, and higher diastolic blood pressure. Reflecting these phenotypes, APAs with mutations had higher CYP11B2 mRNA levels. However, in contrast to APAs in Western countries, Japanese APAs with mutations showed lower CYP11B1, CYP17A1, and CYP11A1 mRNA levels. These findings demonstrated that Japanese APA patients may have distinct features including a higher prevalence of KCNJ5 mutations, no gender difference in the frequency of these mutations, and characteristics similar to the zona glomerulosa.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Characteristics of Japanese aldosterone-producing adenomas with KCNJ5 mutations

et al. 2017

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“…By using in vitro study, Oki et al (2012) demonstrated that a mutation of KCNJ5 (T158A) resulted in decreased ion selectivity of the channel, membrane depolarization, activation of voltage-gated Ca 2+ channels, and increased intracellular Ca 2+ concentration, CYP11B2 overexpression, and aldosterone production. We also have demonstrated that the relative expression levels of CYP11B2 and HSD3B1 mRNAs were significantly higher in KCNJ5-mutated APA (G151R or L168R) than in APA without the KCNJ5 mutilation, while the mRNA of cytochrome P450 17α-hydroxy/17,20-lyase (CYP17A1), a microsomal enzyme essential for the biosynthesis of adrenal and gonadal steroids, was significantly higher in APA without the KCNJ5 mutation than in KCNJ5-mutated APA (G151R or L168R) (Konosu-Fukaya et al 2015). Scholl et al (2013) identified somatic mutations of CACNA1D (G403R and I770M), encoding calcium channel, voltage-dependent, L type, alpha subunit Cav1.3.…”

Section: Somatic Mutations In Aldosterone-driver Genes and Cyp11b2 Exmentioning

confidence: 78%

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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“…In these studies, CYP11B2 immunoreactivity in APA was weak and heterogeneous (Fig. 1A), and the percentage and relative intensity of CYP11B2 immunoreactivity in APA were not necessarily significantly higher than those in the ZG in normal adrenal glands (NA) [22,23]. Therefore, the relative immunointensity and percentage of CYP11B2 immunoreactivity may not necessarily reflect the status of overproduction of aldosterone in APA.…”

Section: The Status Of Aldosterone-producing Enzymes In Pamentioning

confidence: 78%

“…APA tissues in general express relatively high levels of CYP11B2, but StAR mRNA expression is usually not elevated in these tumor tissues [21]. We have recently demonstrated the immunoreactivity of CYP11B2 in cases of APA, using the specific antibodies described above [22,23]. In these studies, CYP11B2 immunoreactivity in APA was weak and heterogeneous (Fig.…”

Section: The Status Of Aldosterone-producing Enzymes In Pamentioning

confidence: 90%