- Email: [email protected]
Aldosterone biosynthesis in the human adrenal cortex and associated disorders
G Model SBMB 4418 No. of Pages 6
Journal of Steroid Biochemistry & Molecular Biology xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Journal of Steroid Biochemistry & Molecular Biology journal homepage: www.elsevier.com/locate/jsbmb
Aldosterone biosynthesis in the human adrenal cortex and associated disorders Yasuhiro Nakamuraa , Yuto Yamazakia , Sachiko Konosu-Fukayaa , Kazue Isea , Fumitoshi Satohb , Hironobu Sasanoa,* a b
Department of Pathology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
A R T I C L E I N F O
A B S T R A C T
Article history: Received 9 February 2015 Received in revised form 15 May 2015 Accepted 16 May 2015 Available online xxx
Aldosterone is one of the mineralocorticoids synthesized and secreted by the adrenal glands, and it plays pivotal roles in regulating extracellular fluid volume and blood pressure. Autonomous excessive aldosterone secretion resulting from adrenocortical diseases is known as primary aldosteronism, and it constitutes one of the most frequent causes of secondary hypertension. Therefore, it is important to understand the molecular mechanisms of aldosterone synthesis in both normal and pathological adrenal tissues. Various factors have been suggested to be involved in regulation of aldosterone biosynthesis, and several adrenocortical cell lines have been developed for use as in vitro models of adrenal aldosteroneproducing cells, for analysis of the underlying molecular mechanisms. In this review, we summarize the available reports on the regulation of aldosterone biosynthesis in the normal adrenal cortex, in associated disorders, and in in vitro models. ã2015 Elsevier Ltd. All rights reserved.
Keywords: Aldosterone Adrenal gland Steroidogenic enzymes
1. Introduction Aldosterone is known to regulate extracellular fluid volume and potassium exchange; it is synthesized in the zona glomerulosa (ZG) of the normal adrenal gland, primarily in response to angiotensin II and serum potassium, resulting in subsequent depolarization and opening of voltage-activated Ca2+-channels, with activation of the calcium signaling pathway [1]. The classic pathway of aldosterone action involves binding to cytosolic mineralocorticoid receptors (MR) and subsequent translocation to the nucleus, followed by transcription and translation of effector proteins involved in regulating the sodium–potassium balance across renal tubular epithelial cells [2,3]. Primary aldosteronism (PA) has been reported to be present in approximately 5–20% of all patients with hypertension [4–6]. In addition, patients with PA are known to show a significantly higher incidence of cardiovascular events than hypertensive subjects [7]. Aldosterone-producing adenoma (APA) and idiopathic hyperaldosteronism (IHA) are two principal causes of PA, both characterized by autonomous aldosterone production from pathological adrenal tissues. In this review, we will focus on the
* Corresponding author. Tel.: +81 22 717 8050; fax: +81 22 717 8051. E-mail address: [email protected] (H. Sasano).
proposed molecular mechanisms of aldosterone biosynthesis in both normal and pathological adrenocortical tissues. 2. The expression of aldosterone-producing enzymes in normal human adrenal glands The adult human adrenal cortex can be divided, histologically speaking, into three different areas; the zona glomerulosa (ZG), the zona fasciculata (ZF), and the zona reticularis (ZR) [8]. Each zone is known to secret different types of adrenocortical steroid hormones: mineralocorticoids in the ZG, glucocorticoids in the ZF, and adrenal androgens in the ZR. However, the functional zonation of the adrenal cortex remains controversial. 11-b-Hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) are regarded as zone-specific steroidogenic enzymes that are involved in the final steps of biosynthesis of cortisol and aldosterone, respectively. Cytochrome P450scc (CYP11A), 3b-hydroxysteroid dehydrogenase (HSD3B), and cytochrome P450, family 21, subfamily A, polypeptide 2 (CYP21A2) are all expressed both in the ZG and the ZF. Adrenocortical cells positive for CYP11B2 and negative for CYP17 are functionally classified as mineralocorticoidproducing cells, whereas cells positive for CYP11B1 and negative for CYP17 are regarded as glucocorticoid-producing cells. GomezSanchez et al. recently reported the development of novel and specific monoclonal antibodies against human CYP11B1 and CYP11B2 [9]. They demonstrated that CYP11B2 immunoreactive
http://dx.doi.org/10.1016/j.jsbmb.2015.05.008 0960-0760/ ã 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Y. Nakamura, et al., Aldosterone biosynthesis in the human adrenal cortex and associated disorders, J. Steroid Biochem. Mol. Biol. (2015), http://dx.doi.org/10.1016/j.jsbmb.2015.05.008
G Model SBMB 4418 No. of Pages 6
2
Y. Nakamura et al. / Journal of Steroid Biochemistry & Molecular Biology xxx (2015) xxx–xxx
cells can be classified into two categories: those scattered in the ZG, and those forming tight clusters [9]. They have also reported that CYP11B1 immunoreactive cells are abundant mainly in the area corresponding to the ZF, and that CYP11B1-immunoreactive cells extend up to the capsule in many parts of the normal human adrenal cortex [9]. 3. Aldosterone production in human fetal adrenal gland In human fetuses, the three layers of the adrenal cortex become morphologically discernible during the final trimester of pregnancy, i.e., the definitive zone (DZ), the transitional zone (TZ), and the fetal zone (FZ). The FZ is the inner zone, in which CYP11A1, CYP17, and sulfokinase are expressed, resulting in the production of DHEAS. The TZ is located between the DZ and the FZ; CYP11A1, CYP17, CYP21A2, and CYP11B1 are expressed in the TZ for cortisol production. The DZ is the outermost zone, and is considered to be the progenitor of the adult adrenal cortex, with the potential to produce mineralocorticoids [10–12]. The expression patterns of steroidogenic enzymes in fetal adrenocortical cells, especially HSD3B and CYP17, indicate that both HSD3B- and CYP17-positive cortical cells preferentially produce cortisol, that HSD3B-positive and CYP17-negative cells preferentially produce mineralocorticoids, and HSD3B-negative and CYP17-positive cells preferentially produce DHEAS. The expression profiles of steroidogenic enzymes in each individual gestational term are summarized in Table 1 [12]. In humans and rhesus monkeys, biosynthesis of glucocorticoids in fetal adrenal glands usually begins at an early stage of gestation [13] and the mineralocorticoid biosynthesis pathway is confined to the definitive zone of the primate fetal adrenal cortex in the third trimester (weeks 18–21) [14]. The biosynthesis of mineralocorticoids requires the expression of CYP11A1, HSD3B type 2 (HSD3B2), CYP11B2, and CYP21A2. Coulter et al. reported the results of an immunohistochemical analysis of the expression profiles of mineralocorticoid synthases in the fetal adrenal cortex [15]. In the early stages of human gestation, CYP21A2 is expressed in several cell islands throughout the DZ, the TZ, and the FZ, but not in the adrenomedullary cells [15]. During weeks 13–24 of gestation, CYP11B1/B2 is present in the TZ and the FZ, but not in the DZ or the adrenomedullary cells. In rhesus monkeys, however, CYP21A2 is expressed more abundantly in the DZ and the TZ than the FZ, and all cells of the TZ and the FZ, but not the DZ, are positive for CYP11B1/B2 staining [15]. The above results all indicate that mineralocorticoid synthesis in the human fetal adrenal glands might begin near term, because the enzymes required for synthesis, such as CYP21A2 and CYP11B2, Table 1 Expression profiles of steroidogenic enzymes in each individual gestational term [12]. Middle gestation Steroidgenic enzymes
DZ
TZ
FZ
P450 scc CYP17 CYP21A2 HSD3B CYP11B1/B2
+ – ++ – –
+ ++ ++ – +
+ + + – +
Steroidgenic enzymes
DZ
TZ
FZ
P450 scc CYP17 CYP21A2 HSD3B CYP11B1/B2
+ – ++ ++ +
+ ++ ++ + ++
+ + + – +
Late gestation
are usually not expressed in the DZ in the early stages of gestation. Late in gestation, CYP11A1, CYP17, HSD3B2, CYP21A2, CYP11B1, and CYP11B2 are all expressed in the DZ [15]. In addition, CYP17 is not usually expressed in the DZ during gestation. Therefore, the DZ could represent the progenitor cells of the ZG of the adult adrenal cortex, but further investigation is required for clarification. In fetuses, approximately 80% of the mineralocorticoids in the blood are derived from the fetal adrenal cortex [16,17]. Near week 16 of gestation, angiotensin II (AT) receptors are expressed in fetal adrenal cortical cells. The AT type 2 receptor is expressed in the FZ, whereas the AT type 1 receptor is expressed in both the FZ and the DZ [18]; however, the biological significance of the differential expression profiles of these receptors remains unknown. In a previous study, aging-related impairment of aldosterone production in the ZG was reported in rats [19]. The plasma concentration of aldosterone was lower in old rats (24 months) than in young rats (3 weeks). In addition, the activity of the aldosterone-producing precursor steroidogenic enzyme and the responsiveness to Ang II, foskolin, and ACTH was lower in old rats. Therefore, the ability to convert steroid precursors to aldosterone declined with aging in rats [19]. Aiba and Fujibayashi summarized the results of immunohistochemical analyses of human resection and autopsy cases, and reported on the aging-related development of the ZG [20]. In newborns to individuals in their third decade, the ZG is well-developed and localized in subcapsular lesions. However, in individuals beyond their fourth decade, the ZG is replaced by lesions known as progenitor zones (ZPs), which express HSD3Bs instead of CYP11B2 [20]. Therefore, adrenocortical remodeling occurs with aging by subcapsular localization of the ZP, which has the potential for bidirectional differentiation, into ZG or ZF, owing to secondary aldosteronism under conditions of high Na, low K, and severe stress [20]. 4. The status of aldosterone-producing enzymes in PA The mechanisms causing the autonomous production of excessive aldosterone in APA have not been fully elucidated at this juncture. However, several studies have indicated that overproduction of steroid hormones in adrenocortical tumors was primarily caused by the disordered and/or disorganized expression of steroidogenic enzymes. 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. 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. CYP11B1 and CYP17 have been reported to be present in APA tumor cells (Fig. 1B and C) [22,23]. In addition, we have also demonstrated that CYP11B1 and CYP17 were co-localized in the great majority of APA tumor cells [22,23] which indicated that these same APA tumor cells could secrete cortisol as well as aldosterone [24,25]. Nanba et al. sub-classified APA into three groups based on semi-quantitative analysis of protein expression: CYP11B2-dominant, CYP11B2/CYP11B1-equivalent, and CYP11B1dominant groups [26]. They reported that the CYP11B2/CYP11B1equivalent and CYP11B1-dominant groups had the potential to produce cortisol autonomously and that the CYP11B2-dominant group showed a potential association with lower serum potassium through mineralocorticoid action [26]. Under normal conditions, CYP11B2 is localized to the ZG, and CYP11B1 is localized exclusively
Please cite this article in press as: Y. Nakamura, et al., Aldosterone biosynthesis in the human adrenal cortex and associated disorders, J. Steroid Biochem. Mol. Biol. (2015), http://dx.doi.org/10.1016/j.jsbmb.2015.05.008
G Model SBMB 4418 No. of Pages 6
Y. Nakamura et al. / Journal of Steroid Biochemistry & Molecular Biology xxx (2015) xxx–xxx
Fig. 1. Immunohistochemical analysis of CYP11B2, CYP11B1, CYP17, HSD3B2 and HSD3B1 in aldosterone-producing adenoma (APA): CYP11B2 shows relatively weak and focal immunostaining in tumoral cells of APA (A). CYP11B1 and CYP17 are focally detectable in tumoral cells of APA (B and C), HSD3B2 is diffusely positive in tumoral cells of APA (D), while HSD3B1 shows heterogeneous immunostaining (E)
to the ZF and the ZR [27]. Therefore, APA is generally composed of a heterogeneous mixture of cortical cells from different adrenal zones, which could explain the above-described tumor tissue expression patterns [28]. Recently, HSD3B has been proposed as another rate-limiting step of aldosterone biosynthesis in the human adrenal gland and associated disorders. Among the isoforms of HSD3B, type 2 (HSD3B2) has been reported to be specifically responsible for overall steroidogenesis in the human adrenal cortex [29], whereas HSD3B type 1 (HSD3B1) is exclusively localized in the ZG of the human adrenal cortex [30]. Doi et al. also demonstrated that HSD3B1 is confined to the ZG, but confirmed the localization of HSD3B2 in the ZF of the non-tumoral adrenal cortex, using immunohistochemistry (IHC) with newly developed mouse monoclonal antibodies against human HSD3B1 and HSD3B2 [30]. In addition, they also reported that APA tumor cells are associated with marked expression of HSD3B2 but not HSD3B1, in contrast to cases of IHA, in which HSD3B1 was expressed exclusively [30]. We also subsequently confirmed that expression of HSD3B2 mRNA was much higher than
3
that of HSD3B1, using quantitative RT-PCR. In addition, HSD3B2 immunoreactivity was reported to be predominant in the great majority of APA cases (Fig. 1D), whereas HSD3B1 was focally detected in APA cells (Fig. 1E). These results indicate that HSD3B2 is the predominant isoform involved in autonomous secretion of aldosterone in APA, whereas HSD3B1 is only involved in some cases. In the ZG of adjacent or non-neoplastic adrenal glands of APA, the relative levels of CYP11B2 immunoreactivity in the hyperplastic ZG were significantly lower than those of NA and IHA [22]. Wang et al. also previously reported that the levels of CYP11B2 mRNA in adjacent adrenal glands of APA were markedly lower than those in APA tumors, using microarray analysis [31]. In addition, HSD3B immunopositivity is markedly weak in the hyperplastic ZG of the attached adrenals of APA. Doi et al. also reported that in non-neoplastic adrenals of APA, these hyperplastic ZG cells were associated with a profound suppression of HSD3B1 and HSD3B2 [30]. The decreased expression levels of these steroidogenic enzymes, including HSD3B and CYP11B2, observed in the hyperplastic ZG of adjacent adrenals in APA did indicate a decreased capacity for aldosterone synthesis, despite the histopathological hyperplasia observed in these tissues [27], which confirmed the concept of “paradoxical hyperplasia of the ZG,” i.e., a hyperplastic ZG in the presence of the markedly suppressed renin– angiotensin system of patients with APA. In the ZG of IHA, the relative abundance of CYP11B2 immunoreactivity was not significantly different from that of NA [22], showing that elevated levels of CYP11B2 in the ZG of IHA may not necessarily indicate aldosterone overproduction; however, the overexpression of the upstream enzymes in the steroid synthesis cascade could play more important roles in the pathophysiology of IHA. The expression of HSD3B in the ZG of IHA has been reported to be markedly elevated compared to that in the ZG of NA [27]. Recently, hyperplastic ZG cells in IHA were demonstrated to show marked HSD3B1 immunoreactivity, whereas HSD3B2-negative and APA tumor cells were diffusely and markedly positive for HSD3B2, as mentioned [30]. These findings indicate that HSD3B1 overexpression may be chiefly responsible for excess aldosterone secretion by increasing production of aldosterone precursors (progesterone and 11-deoxycorticosterone [DOC]) in IHA cases, but further studies are required for clarification [22]. Following molecular pathophysiological analysis, several mutations have been reported to be associated with aldosterone overproduction. Somatic mutation of members of the ATPase gene family, ATP1A1 and ATP2B3, results in autonomous aldosterone secretion [32]. Somatic mutation of the gene for an ATP-sensitive potassium channel (KCNJ5), which encodes the G protein coupled inward rectifier potassium channel 4, is also significantly associated with APA formation [33]. Mutation of these genes is postulated to cause membrane voltage depolarization and subsequent increases in CYP11B2 expression levels, resulting in aldosterone over-production [34]. However, the association
Table 2 Summary of in vitro models of aldosterone synthesis [35–47,50–54]. *; See manuscript. The HAC 15 cell line was established from NCI-H295 cells that showed an improved ACTH response. Cell lines
NCI-H295
NCI-H295R (H295R)
HAC-15
Species Origin Steroidogenic enzymes Responsiveness
Human adrenocortical carcinoma of 48-year-old black female CYP11A, HSD3B2, CYP21, CYP17, CYP11B1, CYP11B2, CYP19, 3bhydroxysteroid sulfotranferase Ang II, K+, (ACTH)
Human Substrain of NCI-H295 CYP11A1, HSD3B2, CYP17, CYP21, CYP11B1, CYP11B2 Ang II, K+, (ACTH), PTH
Human * CYP11A1, HSD3B2, CYP17, CYP21, CYP11B1, CYP11B2 Ang II, K+, Ang III, Ang 1–7, (ACTH)
Please cite this article in press as: Y. Nakamura, et al., Aldosterone biosynthesis in the human adrenal cortex and associated disorders, J. Steroid Biochem. Mol. Biol. (2015), http://dx.doi.org/10.1016/j.jsbmb.2015.05.008
G Model SBMB 4418 No. of Pages 6
4
Y. Nakamura et al. / Journal of Steroid Biochemistry & Molecular Biology xxx (2015) xxx–xxx
between these features of the molecular pathophysiology and histopathology of APA has not been elucidated. Elucidation of the association between these features may clarify the origin of APA. 5. In vitro models of aldosterone production Several models of adrenocortical cells, originally derived from several different species, have been reported. In this section, we focus on several commonly used adrenocortical cell models, and their expression profiles for adrenal steroidogenic enzymes, transcription factors, and regulators of aldosterone synthesis; their responsiveness to angiotensin-II (Ang II), potassium (K+), and ACTH is summarized in Table 2. These in vitro models were isolated from human adrenocortical carcinoma tissue. No in vitro models isolated from the normal adrenal ZG or aldosteroneproducing adenomas have been developed. Thus, the aldosterone biosynthesis of these in vitro models might not reflect that in patients with PA. Aldosterone biosynthesis is divided into the following two main phases: the acute phase, which is regulated by StAR [35], and the chronic phase, which is mainly controlled by CYP11B2 [35]. The acute signaling pathway, which is induced by binding of Ang II to the AT-1 receptor, stimulates aldosterone synthesis via Ca2 + /calmodulin kinase, MAPK, and the cAMP cascade [35]. 5.1. NCI-H295 and NCI-H295R (H295R) cell lines Gazdar et al. first established the NCI-H295 cell line in 1980 [36]. The NCI-H295 cell line was originally derived from an adrenocortical carcinoma of a 48-year-old African American female clinically manifesting with weight loss, acne, facial hirsutism, edema, diarrhea, and cessation of menses [36]. The steroidogenesis of the NCI-H295 cell line was originally evaluated by radioimmunoassay and mass spectrometry. NCI-H295 cell line wasreported to secrete various steroid hormones, with very high concentrations of pregnenolone, 17-hydroxypregnenolone, and dehydroepiandrosterone, and with modest concentrations of 17hydroxyprogesterone, aldosterone, 11-deoxycortisol, progesterone, androstenedione, and dehydroepiandrosterone sulfate [36]. NCI-H295 cell line expresses many adrenocortical steroidogenic enzymes, including StAR, CYP11A, HSD3B2, CYP11B1, CYP21, CYP17, CYP11B2, 3b-hydroxysteroid sulfotransferase, and low levels of aromatase (CYP19) [36,37]. However, Staels et al. reported that NCI-295 cell line did not show any responsiveness to ACTH and Ang II [38]. Subsequently, a number of substrains were developed from the original NCI-H295 cell lines, including the NCI-H295R (H295R) cell line. The H295R cell line is a monolayer cell line, differentiated from original NCI-H295 cells, following three months of culture with a bovine-derived serum substitute which increased cell growth rate with steroidogenic function [39]. The H295R cell line has a shorter doubling time than the original NCI-295 cell line, at two days instead of five [39]. The mRNAs for StAR, CYP11A1, CYP17, CYP21, HSD3B1, HSD3B2, CYP11B1, and CYP11B2 were also reported in H295R cell line [40–42]. Denner et al. reported that mRNA levels of both CYP11B1 and CYP11B2 were increased in the H295R cell line via the protein kinase A pathway [43]. In addition, mRNA levels of CYP11B2 were increased by treatment with angiotensin II and K+ [44,45]. Bird et al. reported that H295R cell line predominantly expresses AT1 receptors [40,41]. H295R cell line has therefore primarily been used for investigation of Ang IImediated aldosterone synthesis. However, it is also true that levels of ACTH receptor expression are markedly low in the H295R cell line. ACTH only slightly stimulates acute, but not chronic, aldosterone synthesis [46].
Nogueira et al. reported rapid responsiveness to Ang II in the H295R and adrenocortical bovine cell lines [47]. They performed microarray analysis of RNA isolated from H295R basal cells and cells treated with Ang II (10 nM) for 1 h. In their study, five genes showed a five-fold upregulation of expression: nuclear receptor subfamily 4, member 2 (NR4A2), NR4A3, v-fos FBJ murine osteosarcoma viral oncogene homolog (FOS), FOSB, and early growth response 4 (EGR4) [47]. Hanley et al. also reported that PTH and PTHRP stimulated aldosterone synthesis in H295R cell line [46]. Genes in the NR4A family are nuclear transcriptional factors, which are involved in steroid production [48,49]. Ota et al. reported that NR4A1 and NR4A2 were expressed in H295R cell line and were involved in aldosterone and cortisol synthesis. Both NR4A1 and NR4A2 enhanced transcription of HSD3B1 [42]. NR4A2 and NR4A3 selectively influenced the expression of CYP11B2 and transcription of HSD3B2, respectively [49]. According to a previous study conducted using cDNA microarray analysis, NR4A2 and NR4A3 mRNA levels were upregulated by Ang II treatment in H295R cells [50]. 5.2. HAC15 cell line Parmar et al. reported the establishment of the HAC (human adrenocortical carcinoma) cell line [51]. However, subsequent single nucleotide polymorphism (SNP) array analysis indicated that the clones (the HAC15 cell line) had been isolated from contaminating H295R cells [52]. The HAC15 cell line has been reported to show a good response to Ang II and K+ treatment, resulting in induction of aldosterone production [52]. In addition, the HAC15 cell line has been reported to show a modest response to ACTH through significant increases in cortisol production and steroidogenic enzyme expression [52]. Compared to NCIH295 cells, HAC cell clones are monoclonal and may provide a more stable steroidogenic phenotype [52]. Oki et al. investigated the responsiveness of HAC15 cell line to Ang II, and reported that aldosterone levels were elevated 3.6-fold by treatment with Ang II (10 nM) for 24 h [53]. The HAC15 cell line has been demonstrated to express StAR and various kinds of steroidogenic enzymes, including CYP11A1, CYP17, CYP21, HSD3B2, CYP11B1, and CYP11B2. Ang II treatment increased the expression levels of StAR, HSD3B2, CYP11B1, and CYP11B2 by 2.4-, 1.9-, 6.9-, and 7.9-fold, respectively, in this cell line, compared to H295R cells [53]. In addition, this cell line has been reported to be responsive to Ang III and metabolites of Ang II [53]. Of particular interest, aldosterone secretion was decreased by losartan alone, among the ATIII blockers employed [53]. HAC15 cell line was also found to be stimulated by both Ang II and III; both were reported to bind to AT1 receptors and to stimulate acute aldosterone synthesis. Synthesis of not just aldosterone, but also cortisol, was reported to be induced by Ang II, ACTH, or forskolin in HAC15 cell line [51,53]. Wang et al. compared CYP11B2 mRNA levels and aldosterone production in human adrenocortical cell lines [54]. qRT-PCR analysis showed that the NCI-H295 cell line had higher expression levels of CYP11B2. In the NCI-295 cell line, mRNA expression of CYP11B2 was almost two-fold compared to that was observed in the HAC 15 cell line [54]. However, aldosterone production was lower than in other cell lines, including the HAC 15 cell line, because of the lower expression of HSD3B2 observed in the NCIH295 cell line [54]. 6. Summary and future perspectives In this review, we have summarized the expression of various factors and regulators involved in adrenal aldosterone production in human adrenal tissues. In future, genomic and epigenomic
Please cite this article in press as: Y. Nakamura, et al., Aldosterone biosynthesis in the human adrenal cortex and associated disorders, J. Steroid Biochem. Mol. Biol. (2015), http://dx.doi.org/10.1016/j.jsbmb.2015.05.008
G Model SBMB 4418 No. of Pages 6
Y. Nakamura et al. / Journal of Steroid Biochemistry & Molecular Biology xxx (2015) xxx–xxx
regulators associated with aldosterone synthesis should be explored. In addition, the adrenocortical cell lines discussed above are far from ideal in vitro models of APA. Therefore, new in vitro models of aldosterone-producing tumors should also be explored in future studies. References [1] A. Splat, L. Hunyay, Control of aldosterone secretion: a model for convergence in cellular signaling pathways, Physiol. Rev. 84 (2004) 489–539. [2] J.R. Sowers, A. Whaley-Connell, M. Epstein, Narrative review: the emerging clinical implications of the role of aldosterone in the metabolic syndrome and resistant hypertension, Ann. Intern. Med. 150 (2009) 776–783. [3] M. Bochud, J. Nussberger, P. Bovet, M.R. Maillard, R.C. Elston, F. Paccaud, C. Shamlaye, M. Burnier, Plasma aldosterone is independently associated with the metabolic syndrome, Hypertension 48 (2006) 239–245. [4] J.W. Funder, Medicine. The genetics of primary aldosteronism, Science 331 (2011) 685–686. [5] G.P. Rossi, G. Bernini, C. Caliumi, G. Desideri, B. Fabris, C. Ferri, C. Ganzaroli, G. Giacchetti, C. Letizia, M. Maccario, F. Mallamaci, M. Mannelli, M.J. Mattarello, A. Moretti, G. Palumbo, G. Parenti, E. Porteri, A. Semplicini, D. Rizzoni, E. Rossi, M. Boscaro, A.C. Pessina, F. Mantero, P.S. Investigators, A prospective study of the prevalence of primary aldosteronism in 1125 hypertensive patients, J. Am. Coll. Cardiol. 48 (2006) 2293–2300. [6] J.S. Williams, G.H. Williams, A. Raji, X. Jeunemaitre, N.J. Brown, P.N. Hopkins, P. R. Conlin, Prevalence of primary hyperaldosteronism in mild to moderate hypertension without hypokalaemia, J. Hum. Hypertens. 20 (2006) 129–136. [7] P. Milliez, X. Girerd, P.F. Plouin, J. Blacher, M.E. Safar, J.J. Mourad, Evidence for an increased rate of cardiovascular events in patients with primary aldosteronism, J. Am. Coll. Cardiol. 45 (2005) 1243–1248. [8] A.M. Neville, M.J. O’Hare, Functional activity of the adrenal cortex, The Human Adrenal Cortex, Springer-Verlag, New York, 1982, pp. 68–98. [9] C.E. Gomez-Sanchez, X. Qi, C. Velarde-Miranda, M.W. Plonczynski, C.R. Parker, W. Rainey, F. Satoh, T. Maekawa, Y. Nakamura, H. Sasano, E.P. Gomez-Sanchez, Development of monoclonal antibodies against human CYP11B1 and CYP11B2, Mol. Cell. Endocrinol. 383 (2014) 111–117. [10] S. Mesiano, C.L. Coulter, R.B. Jaffe, Localization of cytochrome P450 cholesterol side-chain cleavage, cytochrome P450 17a-hydroxylase/17,20-lyase, and 3bhydroxysteroid dehydrogenase isomerase steroidogenic enzymes in human and rhesus monkey fetal adrenal glands: reappraisal of functional zonation, J. Clin. Endocrinol. Metab. 77 (1993) 1184–1189. [11] P.C. Coulter, S. Goldsmith, C.C. Mesiano, M.C. Voytek, J.I. Martin, Functional maturation of the primate fetal adrenal in vivo: 2. Ontogeny of corticosteroid synthesis is dependent upon specific zonal expression of 3b-hydroxysteroid dehydrogenase/isomerase (3bHSD), Endocrinology 137 (1996) 4953–4959. [12] S. Mesiano, R.B. Jaffe, Developmental and functional biology of the primate fetal adrenal cortex, Endocr. Rev. 18 (1997) 378–403. [13] M. Serón-Ferré, C.C. Lawrence, P.K. Siiteri, R.B. Jaffe, Steroid production by the definitive and fetal zones of the human fetal adrenal gland, J. Clin. Endocrinol. Metab. 47 (1978) 603–609. [14] H.P. Nelson, R.W. Kuhn, M.E. Deyman, R.B. Jaffe, Human fetal adrenal definitive and fetal zone metabolism of pregnenolone and corticosterone: alternate biosynthetic pathways and absence of detectable aldosterone synthesis, J. Clin. Endocrinol. Metab. 70 (1990) 693–698. [15] C.L. Coulter, R.B. Jaffe, Functional maturation of the primate fetal adrenal in vivo: 3. Specific zonal localization and developmental regulation of CYP21A2 (P421) and CYP11B1/CYP11B2 (P411/aldosterone synthase) lead to integrated concept of zonal and temporal steroid biosynthesis, Endocrinology 139 (1998) 5144–5150. [16] F. Bayard, I.G. Ances, A.J. Tapper, V.V. Weldon, A. Kowarski, C.J. Migeon, Transplacental passage and fetal secretion of aldosterone, J. Clin. Invest. 49 (1970) 1389–1393. [17] M. Serón-Ferré, E.G. Biglieri, R.B. Jaffe, Regulation of mineralocorticoid secretion by the superfused fetal monkey adrenal gland: lack of stimulation of aldosterone by ACTH, J. Dev. Physiol. 13 (1990) 33–36. [18] L. Breault, J.G. Lehoux, N. Gallo-Payet, The angiotensin AT2 receptor is present in the human fetal adrenal gland throughout the second trimester of gestation, J. Clin. Endocrinol. Metab. 81 (1996) 3914–3922. [19] A.J. Harper, J.E. Buster, P.R. Casson, Changes in adrenocortical function with aging and therapeutic implications, Semin. Reprod. Endocrinol. 17 (1999) 327– 338. [20] M. Aiba, M. Fujibayashi, Alteration of subcapsular adrenocortical zonation in humans with aging: the progenitor zone predominates over the previously well-developed zona glomerulosa after 40 years of age, J. Histochem. Cytochem. 59 (2011) 557–564. [21] M.H. Bassett, B. Mayhew, K. Rehman, P.C. White, F. Mantero, G. Arnaldi, P.M. Stewart, I. Bujalska, W.E. Rainey, Expression profiles for steroidogenic enzymes in adrenocortical disease, J. Clin. Endocrinol. Metab. 90 (2005) 5446–5455. [22] Y. Nakamura, T. Maekawa, S.J. Felizola, F. Satoh, X. Qi, C. Velarde-Miranda, M.W. Plonczynski, K. Ise, K. Kikuchi, W.E. Rainey, E.P. Gomez-Sanchez, C.E. GomezSanchez, H. Sasano, Adrenal CYP11B1/2 expression in primary aldosteronism: immunohistochemical analysis using novel monoclonal antibodies, Mol. Cell. Endocrinol. 392 (2014) 73–79.
5
[23] S. Konosu-Fukaya, Y. Nakamura, F. Satoh, S.J. Felizola, T. Maekawa, Y. Ono, R. Morimoto, K. Ise, K.I. Takeda, K. Katsu, F. Fujishima, A. Kasajima, M. Watanabe, Y. Arai, E.P. Gomez-Sanchez, C.E. Gomez-Sanchez, M. Doi, H. Okamura, H. Sasano, 3Beta-hydroxysteroid dehydrogenase isoforms in human aldosteroneproducing adenoma, Mol. Cell. Endocrinol. (2015) , doi:http://dx.doi.org/ 10.1016/j.mce.2014.10.008. [24] F. Fallo, C. Bertello, D. Tizzani, A. Fassina, S. Boulkroun, N. Sonino, S. Monticone, A. Viola, F. Veglio, P. Mulatero, Concurrent primary aldosteronism and subclinical cortisol hypersecretion: a prospective study, J. Hypertens. 29 (2011) 1773–1777. [25] K. Hiraishi, T. Yoshimoto, K. Tsuchiya, I. Minami, M. Doi, H. Izumiyama, H. Sasano, Y. Hirata, Clinicopathological features of primary aldosteronism associated with subclinical Cushing’s syndrome, Endocr. J. 58 (2011) 543–551. [26] K. Nanba, M. Tsuiki, K. Sawai, K. Mukai, K. Nishimoto, T. Usui, T. Tagami, H. Okuno, T. Yamamoto, A. Shimatsu, T. Katabami, A. Okumura, G. Kawa, A. Tanabe, M. Naruse, Histopathological diagnosis of primary aldosteronism using CYP11B2 immunohistochemistry, J. Clin. Endocrinol. Metab. 98 (2013) 1567–1574. [27] H. Sasano, Localization of steroidogenic enzymes in adrenal cortex and its disorders, Endocr. J. 41 (1994) 471–482. [28] E.A. Azizan, B.Y. Lam, S.J. Newhouse, J. Zhou, R.E. Kuc, J. Clarke, L. Happerfield, A. Marker, G.J. Hoffman, M.J. Brown, Microarray, qPCR, and KCNJ5 sequencing of aldosterone-producing adenomas reveal differences in genotype and phenotype between zona glomerulosa- and zona fasciculata-like tumors, J. Clin. Endocrinol. Metab. 97 (2012) E819–E829. [29] J. Simard, M.L. Ricketts, S. Gingras, P. Soucy, F.A. Feltus, M.H. Melner, Molecular biology of the 3beta-hydroxysteroid dehydrogenase/delta5–delta4 isomerase gene family, Endocr. Rev. 26 (2005) 525–582. [30] M. Doi, F. Satoh, T. Maekawa, Y. Nakamura, J.M. Fustin, M. Tainaka, Y. Hotta, Y. Takahashi, R. Morimoto, K. Takase, S. Ito, H. Sasano, H. Okamura, Isoformspecific monoclonal antibodies against 3beta-hydroxysteroid dehydrogenase/ isomerase family provide markers for subclassification of human primary aldosteronism, J. Clin. Endocrinol. Metab. 99 (2014) E257–E262. [31] T. Wang, F. Satoh, R. Morimoto, Y. Nakamura, H. Sasano, R.J. Auchus, M.A. Edwards, W.E. Rainey, Gene expression profiles in aldosterone-producing adenomas and adjacent adrenal glands, Eur. J. Endocrinol. 164 (2011) 613–619. [32] F. Beuschlein, S. Boulkroun, A. Osswald, T. Wieland, H.N. Nielsen, U.D. Lichtenauer, D. Penton, V.R. Schack, L. Amar, E. Fischer, A. Walther, P. Tauber, T. Schwarzmayr, S. Diener, E. Graf, B. Allolio, B. Samson-Couterie, A. Benecke, M. Quinkler, F. Fallo, P.F. Plouin, F. Mantero, T. Meitinger, P. Mulatero, X. Jeunemaitre, R. Warth, B. Vilsen, M.C. Zennaro, T.M. Strom, M. Reincke, Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary hypertension, Nat. Genet. 45 (2013) 440–444 (444e441-442). [33] S. Boulkroun, J.F. Golib Dzib, B. Samson-Couterie, F.L. Rosa, A.J. Rickard, T. Meatchi, L. Amar, A. Benecke, M.C. Zennaro, KCNJ5 mutations in aldosterone producing adenoma and relationship with adrenal cortex remodeling, Mol. Cell. Endocrinol. 371 (2013) 221–227. [34] T.A. Williams, S. Monticone, V.R. Schack, J. Stindl, J. Burrello, F. Buffolo, L. Annaratone, I. Castellano, F. Beuschlein, M. Reincke, B. Lucatello, V. Ronconi, F. Fallo, G. Bernini, M. Maccario, G. Giacchetti, F. Veglio, R. Warth, B. Vilsen, P. Mulatero, Somatic ATP1A1, ATP2B3, and KCNJ5 mutations in aldosteroneproducing adenomas, Hypertension 63 (2014) 188–195. [35] M.H. Bassett, P.C. White, W.E. Rainey, The regulation of aldosterone synthase expression, Mol. Cell. Endocrinol. 217 (2004) 67–74. [36] A.F. Gazdar, H.K. Oie, C.H. Shackleton, T.J. Chen, C.E. Myers, G.P. Chrousos, M.F. Brennan, C.A. Stein, R.V. La Rocca, Establishment and characterization of a human adrenocortical carcinoma cell line that expresses multiple pathways of steroid biosynthesis, Cancer Res. 50 (1990) 5488–5496. [37] W.E. Rainey, K. Sanera, B.P. Schimmer, Adrenocortical cell lines, Mol. Cell. Endocrinol. 228 (2004) 23–38. [38] B. Staels, D.W. Hum, W.L. Miller, Regulation of steroidogenesis in NCIH295 cells: a cellular model of the human fetal adrenal, Mol. Endocrinol. 7 (1993) 423–433. [39] P.J. Hornsby, J.M. McAllister, Culturing steroidogenic cells, Methods Enzymol. 206 (1991) 371–380. [40] I.M. Bird, N.A. Hanley, R.A. Word, J.M. Mathis, J.L. McCarthy, J.I. Mason, W.E. Rainey, Human NCI-H295 adrenocortical carcinoma cells: a model for angiotensin-II-responsive aldosterone secretion, Endocrinology 133 (1993) 1555–1561. [41] I.M. Bird, J.I. Mason, W.E. Rainey, Regulation of type 1 angiotensin II receptor messenger ribonucleic acid expression in human adrenocortical carcinoma H295 cells, Endocrinology 134 (1994) 2468–2474. [42] T. Ota, M. Doi, F. Yamazaki, D. Yarimizu, K. Okada, I. Murai, H. Hayashi, S. Kunisue, Y. Nakagawa, H. Okamura, Angiotensin II triggers expression of the adrenal gland zona glomerulosa-specific 3b-hydroxysteroid dehydrogenase isoenzyme through de novo protein synthesis of the orphan nuclear receptors NGFIB and NURR1, Mol. Cell. Biol. 34 (2014) 3880–3894. [43] K. Denner, W.E. Rainey, V. Pezzi, I.M. Bird, R. Bernhardt, J.M. Mathis, Differential regulation of 11 beta-hydroxylase and aldosterone synthase in human adrenocortical H295R cells, Mol. Cell. Endocrinol. 121 (1996) 87–91. [44] O.B. Holland, J.M. Mathis, I.M. Bird, W.E. Rainey, Angiotensin increases aldosterone synthase mRNA levels in human NCI-H295 cells, Mol. Cell. Endocrinol. 94 (1993) 9–13. [45] I.M. Bird, J.M. Mathis, J.I. Mason, W.E. Rainey, Ca(2+)-regulated expression of steroid hydroxylases in H295R human adrenocortical cells, Endocrinology 136 (1995) 5677–5684.
Please cite this article in press as: Y. Nakamura, et al., Aldosterone biosynthesis in the human adrenal cortex and associated disorders, J. Steroid Biochem. Mol. Biol. (2015), http://dx.doi.org/10.1016/j.jsbmb.2015.05.008
G Model SBMB 4418 No. of Pages 6
6
Y. Nakamura et al. / Journal of Steroid Biochemistry & Molecular Biology xxx (2015) xxx–xxx
[46] N.A. Hanley, R.M. Wester, B.R. Carr, W.E. Rainey, Parathyroid hormone and parathyroid hormone-related peptide stimulate aldosterone production in the human adrenocortical cell line, NCI-H295, Endocr. J. 1 (1993) 447–450. [47] E.F. Nogueira, C.A. Vargas, M. Otis, N. Gallo-Payet, W.B. Bollag, W.E. Rainey, Angiotensin-II acute regulation of rapid response genes in human, bovine, and rat adrenocortical cells, J. Mol. Endocrinol. 39 (2007) 365–374. [48] H.C. Hsu, T. Zhou, J.D. Mountz, Nur77 family of nuclear hormone receptors, Curr. Drug Targets Inflamm. Allergy 3 (2004) 413–423. [49] M.H. Bassett, P.C. White, W.E. Rainey, A role for the NGFI-B family in adrenal zonation and adrenocortical disease, Endocr. Res. 30 (2004) 567–574. [50] D.G. Romero, M. Plonczynski, G.R. Vergara, E.P. Gomez-Sanchez, C.E. GomezSanchez, Angiotensin II early regulated genes in H295R human adrenocortical cells, Physiol. Genomics 19 (2004) 106–116.
[51] J. Parmar, R.E. Key, W.E. Rainey, Development of an adrenocorticotropinresponsive human adrenocortical carcinoma cell line, J. Clin. Endocrinol. Metab. 93 (2008) 4542–4546. [52] T. Wang, W.E. Rainey, Human adrenocortical carcinoma cell lines, Mol. Cell. Endocrinol. 351 (2012) 58–65. [53 K. Oki, P.G. Kopf, W.B. Campbel, M.L. l Lam, T. Yamazaki, C.E. Gomez-Sanchez, E. P. Gomez-Sanchez, Angiotensin II and III metabolism and effects on steroid production in the HAC15 human adrenocortical cell line, Endocrinology 154 (2013) 214–221. [54] T. Wang, J.G. Rowland, J. Parmer, M. Nesterova, T. Seki, W.E. Rainey, Comparison of aldosterone production among human adrenocortical cell lines, Horm. Metab. Res. 44 (2012) 245–250.
Please cite this article in press as: Y. Nakamura, et al., Aldosterone biosynthesis in the human adrenal cortex and associated disorders, J. Steroid Biochem. Mol. Biol. (2015), http://dx.doi.org/10.1016/j.jsbmb.2015.05.008
Journal of Steroid Biochemistry & Molecular Biology xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Journal of Steroid Biochemistry & Molecular Biology journal homepage: www.elsevier.com/locate/jsbmb
Aldosterone biosynthesis in the human adrenal cortex and associated disorders Yasuhiro Nakamuraa , Yuto Yamazakia , Sachiko Konosu-Fukayaa , Kazue Isea , Fumitoshi Satohb , Hironobu Sasanoa,* a b
Department of Pathology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
A R T I C L E I N F O
A B S T R A C T
Article history: Received 9 February 2015 Received in revised form 15 May 2015 Accepted 16 May 2015 Available online xxx
Aldosterone is one of the mineralocorticoids synthesized and secreted by the adrenal glands, and it plays pivotal roles in regulating extracellular fluid volume and blood pressure. Autonomous excessive aldosterone secretion resulting from adrenocortical diseases is known as primary aldosteronism, and it constitutes one of the most frequent causes of secondary hypertension. Therefore, it is important to understand the molecular mechanisms of aldosterone synthesis in both normal and pathological adrenal tissues. Various factors have been suggested to be involved in regulation of aldosterone biosynthesis, and several adrenocortical cell lines have been developed for use as in vitro models of adrenal aldosteroneproducing cells, for analysis of the underlying molecular mechanisms. In this review, we summarize the available reports on the regulation of aldosterone biosynthesis in the normal adrenal cortex, in associated disorders, and in in vitro models. ã2015 Elsevier Ltd. All rights reserved.
Keywords: Aldosterone Adrenal gland Steroidogenic enzymes
1. Introduction Aldosterone is known to regulate extracellular fluid volume and potassium exchange; it is synthesized in the zona glomerulosa (ZG) of the normal adrenal gland, primarily in response to angiotensin II and serum potassium, resulting in subsequent depolarization and opening of voltage-activated Ca2+-channels, with activation of the calcium signaling pathway [1]. The classic pathway of aldosterone action involves binding to cytosolic mineralocorticoid receptors (MR) and subsequent translocation to the nucleus, followed by transcription and translation of effector proteins involved in regulating the sodium–potassium balance across renal tubular epithelial cells [2,3]. Primary aldosteronism (PA) has been reported to be present in approximately 5–20% of all patients with hypertension [4–6]. In addition, patients with PA are known to show a significantly higher incidence of cardiovascular events than hypertensive subjects [7]. Aldosterone-producing adenoma (APA) and idiopathic hyperaldosteronism (IHA) are two principal causes of PA, both characterized by autonomous aldosterone production from pathological adrenal tissues. In this review, we will focus on the
* Corresponding author. Tel.: +81 22 717 8050; fax: +81 22 717 8051. E-mail address: [email protected] (H. Sasano).
proposed molecular mechanisms of aldosterone biosynthesis in both normal and pathological adrenocortical tissues. 2. The expression of aldosterone-producing enzymes in normal human adrenal glands The adult human adrenal cortex can be divided, histologically speaking, into three different areas; the zona glomerulosa (ZG), the zona fasciculata (ZF), and the zona reticularis (ZR) [8]. Each zone is known to secret different types of adrenocortical steroid hormones: mineralocorticoids in the ZG, glucocorticoids in the ZF, and adrenal androgens in the ZR. However, the functional zonation of the adrenal cortex remains controversial. 11-b-Hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) are regarded as zone-specific steroidogenic enzymes that are involved in the final steps of biosynthesis of cortisol and aldosterone, respectively. Cytochrome P450scc (CYP11A), 3b-hydroxysteroid dehydrogenase (HSD3B), and cytochrome P450, family 21, subfamily A, polypeptide 2 (CYP21A2) are all expressed both in the ZG and the ZF. Adrenocortical cells positive for CYP11B2 and negative for CYP17 are functionally classified as mineralocorticoidproducing cells, whereas cells positive for CYP11B1 and negative for CYP17 are regarded as glucocorticoid-producing cells. GomezSanchez et al. recently reported the development of novel and specific monoclonal antibodies against human CYP11B1 and CYP11B2 [9]. They demonstrated that CYP11B2 immunoreactive
http://dx.doi.org/10.1016/j.jsbmb.2015.05.008 0960-0760/ ã 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Y. Nakamura, et al., Aldosterone biosynthesis in the human adrenal cortex and associated disorders, J. Steroid Biochem. Mol. Biol. (2015), http://dx.doi.org/10.1016/j.jsbmb.2015.05.008
G Model SBMB 4418 No. of Pages 6
2
Y. Nakamura et al. / Journal of Steroid Biochemistry & Molecular Biology xxx (2015) xxx–xxx
cells can be classified into two categories: those scattered in the ZG, and those forming tight clusters [9]. They have also reported that CYP11B1 immunoreactive cells are abundant mainly in the area corresponding to the ZF, and that CYP11B1-immunoreactive cells extend up to the capsule in many parts of the normal human adrenal cortex [9]. 3. Aldosterone production in human fetal adrenal gland In human fetuses, the three layers of the adrenal cortex become morphologically discernible during the final trimester of pregnancy, i.e., the definitive zone (DZ), the transitional zone (TZ), and the fetal zone (FZ). The FZ is the inner zone, in which CYP11A1, CYP17, and sulfokinase are expressed, resulting in the production of DHEAS. The TZ is located between the DZ and the FZ; CYP11A1, CYP17, CYP21A2, and CYP11B1 are expressed in the TZ for cortisol production. The DZ is the outermost zone, and is considered to be the progenitor of the adult adrenal cortex, with the potential to produce mineralocorticoids [10–12]. The expression patterns of steroidogenic enzymes in fetal adrenocortical cells, especially HSD3B and CYP17, indicate that both HSD3B- and CYP17-positive cortical cells preferentially produce cortisol, that HSD3B-positive and CYP17-negative cells preferentially produce mineralocorticoids, and HSD3B-negative and CYP17-positive cells preferentially produce DHEAS. The expression profiles of steroidogenic enzymes in each individual gestational term are summarized in Table 1 [12]. In humans and rhesus monkeys, biosynthesis of glucocorticoids in fetal adrenal glands usually begins at an early stage of gestation [13] and the mineralocorticoid biosynthesis pathway is confined to the definitive zone of the primate fetal adrenal cortex in the third trimester (weeks 18–21) [14]. The biosynthesis of mineralocorticoids requires the expression of CYP11A1, HSD3B type 2 (HSD3B2), CYP11B2, and CYP21A2. Coulter et al. reported the results of an immunohistochemical analysis of the expression profiles of mineralocorticoid synthases in the fetal adrenal cortex [15]. In the early stages of human gestation, CYP21A2 is expressed in several cell islands throughout the DZ, the TZ, and the FZ, but not in the adrenomedullary cells [15]. During weeks 13–24 of gestation, CYP11B1/B2 is present in the TZ and the FZ, but not in the DZ or the adrenomedullary cells. In rhesus monkeys, however, CYP21A2 is expressed more abundantly in the DZ and the TZ than the FZ, and all cells of the TZ and the FZ, but not the DZ, are positive for CYP11B1/B2 staining [15]. The above results all indicate that mineralocorticoid synthesis in the human fetal adrenal glands might begin near term, because the enzymes required for synthesis, such as CYP21A2 and CYP11B2, Table 1 Expression profiles of steroidogenic enzymes in each individual gestational term [12]. Middle gestation Steroidgenic enzymes
DZ
TZ
FZ
P450 scc CYP17 CYP21A2 HSD3B CYP11B1/B2
+ – ++ – –
+ ++ ++ – +
+ + + – +
Steroidgenic enzymes
DZ
TZ
FZ
P450 scc CYP17 CYP21A2 HSD3B CYP11B1/B2
+ – ++ ++ +
+ ++ ++ + ++
+ + + – +
Late gestation
are usually not expressed in the DZ in the early stages of gestation. Late in gestation, CYP11A1, CYP17, HSD3B2, CYP21A2, CYP11B1, and CYP11B2 are all expressed in the DZ [15]. In addition, CYP17 is not usually expressed in the DZ during gestation. Therefore, the DZ could represent the progenitor cells of the ZG of the adult adrenal cortex, but further investigation is required for clarification. In fetuses, approximately 80% of the mineralocorticoids in the blood are derived from the fetal adrenal cortex [16,17]. Near week 16 of gestation, angiotensin II (AT) receptors are expressed in fetal adrenal cortical cells. The AT type 2 receptor is expressed in the FZ, whereas the AT type 1 receptor is expressed in both the FZ and the DZ [18]; however, the biological significance of the differential expression profiles of these receptors remains unknown. In a previous study, aging-related impairment of aldosterone production in the ZG was reported in rats [19]. The plasma concentration of aldosterone was lower in old rats (24 months) than in young rats (3 weeks). In addition, the activity of the aldosterone-producing precursor steroidogenic enzyme and the responsiveness to Ang II, foskolin, and ACTH was lower in old rats. Therefore, the ability to convert steroid precursors to aldosterone declined with aging in rats [19]. Aiba and Fujibayashi summarized the results of immunohistochemical analyses of human resection and autopsy cases, and reported on the aging-related development of the ZG [20]. In newborns to individuals in their third decade, the ZG is well-developed and localized in subcapsular lesions. However, in individuals beyond their fourth decade, the ZG is replaced by lesions known as progenitor zones (ZPs), which express HSD3Bs instead of CYP11B2 [20]. Therefore, adrenocortical remodeling occurs with aging by subcapsular localization of the ZP, which has the potential for bidirectional differentiation, into ZG or ZF, owing to secondary aldosteronism under conditions of high Na, low K, and severe stress [20]. 4. The status of aldosterone-producing enzymes in PA The mechanisms causing the autonomous production of excessive aldosterone in APA have not been fully elucidated at this juncture. However, several studies have indicated that overproduction of steroid hormones in adrenocortical tumors was primarily caused by the disordered and/or disorganized expression of steroidogenic enzymes. 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. 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. CYP11B1 and CYP17 have been reported to be present in APA tumor cells (Fig. 1B and C) [22,23]. In addition, we have also demonstrated that CYP11B1 and CYP17 were co-localized in the great majority of APA tumor cells [22,23] which indicated that these same APA tumor cells could secrete cortisol as well as aldosterone [24,25]. Nanba et al. sub-classified APA into three groups based on semi-quantitative analysis of protein expression: CYP11B2-dominant, CYP11B2/CYP11B1-equivalent, and CYP11B1dominant groups [26]. They reported that the CYP11B2/CYP11B1equivalent and CYP11B1-dominant groups had the potential to produce cortisol autonomously and that the CYP11B2-dominant group showed a potential association with lower serum potassium through mineralocorticoid action [26]. Under normal conditions, CYP11B2 is localized to the ZG, and CYP11B1 is localized exclusively
Please cite this article in press as: Y. Nakamura, et al., Aldosterone biosynthesis in the human adrenal cortex and associated disorders, J. Steroid Biochem. Mol. Biol. (2015), http://dx.doi.org/10.1016/j.jsbmb.2015.05.008
G Model SBMB 4418 No. of Pages 6
Y. Nakamura et al. / Journal of Steroid Biochemistry & Molecular Biology xxx (2015) xxx–xxx
Fig. 1. Immunohistochemical analysis of CYP11B2, CYP11B1, CYP17, HSD3B2 and HSD3B1 in aldosterone-producing adenoma (APA): CYP11B2 shows relatively weak and focal immunostaining in tumoral cells of APA (A). CYP11B1 and CYP17 are focally detectable in tumoral cells of APA (B and C), HSD3B2 is diffusely positive in tumoral cells of APA (D), while HSD3B1 shows heterogeneous immunostaining (E)
to the ZF and the ZR [27]. Therefore, APA is generally composed of a heterogeneous mixture of cortical cells from different adrenal zones, which could explain the above-described tumor tissue expression patterns [28]. Recently, HSD3B has been proposed as another rate-limiting step of aldosterone biosynthesis in the human adrenal gland and associated disorders. Among the isoforms of HSD3B, type 2 (HSD3B2) has been reported to be specifically responsible for overall steroidogenesis in the human adrenal cortex [29], whereas HSD3B type 1 (HSD3B1) is exclusively localized in the ZG of the human adrenal cortex [30]. Doi et al. also demonstrated that HSD3B1 is confined to the ZG, but confirmed the localization of HSD3B2 in the ZF of the non-tumoral adrenal cortex, using immunohistochemistry (IHC) with newly developed mouse monoclonal antibodies against human HSD3B1 and HSD3B2 [30]. In addition, they also reported that APA tumor cells are associated with marked expression of HSD3B2 but not HSD3B1, in contrast to cases of IHA, in which HSD3B1 was expressed exclusively [30]. We also subsequently confirmed that expression of HSD3B2 mRNA was much higher than
3
that of HSD3B1, using quantitative RT-PCR. In addition, HSD3B2 immunoreactivity was reported to be predominant in the great majority of APA cases (Fig. 1D), whereas HSD3B1 was focally detected in APA cells (Fig. 1E). These results indicate that HSD3B2 is the predominant isoform involved in autonomous secretion of aldosterone in APA, whereas HSD3B1 is only involved in some cases. In the ZG of adjacent or non-neoplastic adrenal glands of APA, the relative levels of CYP11B2 immunoreactivity in the hyperplastic ZG were significantly lower than those of NA and IHA [22]. Wang et al. also previously reported that the levels of CYP11B2 mRNA in adjacent adrenal glands of APA were markedly lower than those in APA tumors, using microarray analysis [31]. In addition, HSD3B immunopositivity is markedly weak in the hyperplastic ZG of the attached adrenals of APA. Doi et al. also reported that in non-neoplastic adrenals of APA, these hyperplastic ZG cells were associated with a profound suppression of HSD3B1 and HSD3B2 [30]. The decreased expression levels of these steroidogenic enzymes, including HSD3B and CYP11B2, observed in the hyperplastic ZG of adjacent adrenals in APA did indicate a decreased capacity for aldosterone synthesis, despite the histopathological hyperplasia observed in these tissues [27], which confirmed the concept of “paradoxical hyperplasia of the ZG,” i.e., a hyperplastic ZG in the presence of the markedly suppressed renin– angiotensin system of patients with APA. In the ZG of IHA, the relative abundance of CYP11B2 immunoreactivity was not significantly different from that of NA [22], showing that elevated levels of CYP11B2 in the ZG of IHA may not necessarily indicate aldosterone overproduction; however, the overexpression of the upstream enzymes in the steroid synthesis cascade could play more important roles in the pathophysiology of IHA. The expression of HSD3B in the ZG of IHA has been reported to be markedly elevated compared to that in the ZG of NA [27]. Recently, hyperplastic ZG cells in IHA were demonstrated to show marked HSD3B1 immunoreactivity, whereas HSD3B2-negative and APA tumor cells were diffusely and markedly positive for HSD3B2, as mentioned [30]. These findings indicate that HSD3B1 overexpression may be chiefly responsible for excess aldosterone secretion by increasing production of aldosterone precursors (progesterone and 11-deoxycorticosterone [DOC]) in IHA cases, but further studies are required for clarification [22]. Following molecular pathophysiological analysis, several mutations have been reported to be associated with aldosterone overproduction. Somatic mutation of members of the ATPase gene family, ATP1A1 and ATP2B3, results in autonomous aldosterone secretion [32]. Somatic mutation of the gene for an ATP-sensitive potassium channel (KCNJ5), which encodes the G protein coupled inward rectifier potassium channel 4, is also significantly associated with APA formation [33]. Mutation of these genes is postulated to cause membrane voltage depolarization and subsequent increases in CYP11B2 expression levels, resulting in aldosterone over-production [34]. However, the association
Table 2 Summary of in vitro models of aldosterone synthesis [35–47,50–54]. *; See manuscript. The HAC 15 cell line was established from NCI-H295 cells that showed an improved ACTH response. Cell lines
NCI-H295
NCI-H295R (H295R)
HAC-15
Species Origin Steroidogenic enzymes Responsiveness
Human adrenocortical carcinoma of 48-year-old black female CYP11A, HSD3B2, CYP21, CYP17, CYP11B1, CYP11B2, CYP19, 3bhydroxysteroid sulfotranferase Ang II, K+, (ACTH)
Human Substrain of NCI-H295 CYP11A1, HSD3B2, CYP17, CYP21, CYP11B1, CYP11B2 Ang II, K+, (ACTH), PTH
Human * CYP11A1, HSD3B2, CYP17, CYP21, CYP11B1, CYP11B2 Ang II, K+, Ang III, Ang 1–7, (ACTH)
Please cite this article in press as: Y. Nakamura, et al., Aldosterone biosynthesis in the human adrenal cortex and associated disorders, J. Steroid Biochem. Mol. Biol. (2015), http://dx.doi.org/10.1016/j.jsbmb.2015.05.008
G Model SBMB 4418 No. of Pages 6
4
Y. Nakamura et al. / Journal of Steroid Biochemistry & Molecular Biology xxx (2015) xxx–xxx
between these features of the molecular pathophysiology and histopathology of APA has not been elucidated. Elucidation of the association between these features may clarify the origin of APA. 5. In vitro models of aldosterone production Several models of adrenocortical cells, originally derived from several different species, have been reported. In this section, we focus on several commonly used adrenocortical cell models, and their expression profiles for adrenal steroidogenic enzymes, transcription factors, and regulators of aldosterone synthesis; their responsiveness to angiotensin-II (Ang II), potassium (K+), and ACTH is summarized in Table 2. These in vitro models were isolated from human adrenocortical carcinoma tissue. No in vitro models isolated from the normal adrenal ZG or aldosteroneproducing adenomas have been developed. Thus, the aldosterone biosynthesis of these in vitro models might not reflect that in patients with PA. Aldosterone biosynthesis is divided into the following two main phases: the acute phase, which is regulated by StAR [35], and the chronic phase, which is mainly controlled by CYP11B2 [35]. The acute signaling pathway, which is induced by binding of Ang II to the AT-1 receptor, stimulates aldosterone synthesis via Ca2 + /calmodulin kinase, MAPK, and the cAMP cascade [35]. 5.1. NCI-H295 and NCI-H295R (H295R) cell lines Gazdar et al. first established the NCI-H295 cell line in 1980 [36]. The NCI-H295 cell line was originally derived from an adrenocortical carcinoma of a 48-year-old African American female clinically manifesting with weight loss, acne, facial hirsutism, edema, diarrhea, and cessation of menses [36]. The steroidogenesis of the NCI-H295 cell line was originally evaluated by radioimmunoassay and mass spectrometry. NCI-H295 cell line wasreported to secrete various steroid hormones, with very high concentrations of pregnenolone, 17-hydroxypregnenolone, and dehydroepiandrosterone, and with modest concentrations of 17hydroxyprogesterone, aldosterone, 11-deoxycortisol, progesterone, androstenedione, and dehydroepiandrosterone sulfate [36]. NCI-H295 cell line expresses many adrenocortical steroidogenic enzymes, including StAR, CYP11A, HSD3B2, CYP11B1, CYP21, CYP17, CYP11B2, 3b-hydroxysteroid sulfotransferase, and low levels of aromatase (CYP19) [36,37]. However, Staels et al. reported that NCI-295 cell line did not show any responsiveness to ACTH and Ang II [38]. Subsequently, a number of substrains were developed from the original NCI-H295 cell lines, including the NCI-H295R (H295R) cell line. The H295R cell line is a monolayer cell line, differentiated from original NCI-H295 cells, following three months of culture with a bovine-derived serum substitute which increased cell growth rate with steroidogenic function [39]. The H295R cell line has a shorter doubling time than the original NCI-295 cell line, at two days instead of five [39]. The mRNAs for StAR, CYP11A1, CYP17, CYP21, HSD3B1, HSD3B2, CYP11B1, and CYP11B2 were also reported in H295R cell line [40–42]. Denner et al. reported that mRNA levels of both CYP11B1 and CYP11B2 were increased in the H295R cell line via the protein kinase A pathway [43]. In addition, mRNA levels of CYP11B2 were increased by treatment with angiotensin II and K+ [44,45]. Bird et al. reported that H295R cell line predominantly expresses AT1 receptors [40,41]. H295R cell line has therefore primarily been used for investigation of Ang IImediated aldosterone synthesis. However, it is also true that levels of ACTH receptor expression are markedly low in the H295R cell line. ACTH only slightly stimulates acute, but not chronic, aldosterone synthesis [46].
Nogueira et al. reported rapid responsiveness to Ang II in the H295R and adrenocortical bovine cell lines [47]. They performed microarray analysis of RNA isolated from H295R basal cells and cells treated with Ang II (10 nM) for 1 h. In their study, five genes showed a five-fold upregulation of expression: nuclear receptor subfamily 4, member 2 (NR4A2), NR4A3, v-fos FBJ murine osteosarcoma viral oncogene homolog (FOS), FOSB, and early growth response 4 (EGR4) [47]. Hanley et al. also reported that PTH and PTHRP stimulated aldosterone synthesis in H295R cell line [46]. Genes in the NR4A family are nuclear transcriptional factors, which are involved in steroid production [48,49]. Ota et al. reported that NR4A1 and NR4A2 were expressed in H295R cell line and were involved in aldosterone and cortisol synthesis. Both NR4A1 and NR4A2 enhanced transcription of HSD3B1 [42]. NR4A2 and NR4A3 selectively influenced the expression of CYP11B2 and transcription of HSD3B2, respectively [49]. According to a previous study conducted using cDNA microarray analysis, NR4A2 and NR4A3 mRNA levels were upregulated by Ang II treatment in H295R cells [50]. 5.2. HAC15 cell line Parmar et al. reported the establishment of the HAC (human adrenocortical carcinoma) cell line [51]. However, subsequent single nucleotide polymorphism (SNP) array analysis indicated that the clones (the HAC15 cell line) had been isolated from contaminating H295R cells [52]. The HAC15 cell line has been reported to show a good response to Ang II and K+ treatment, resulting in induction of aldosterone production [52]. In addition, the HAC15 cell line has been reported to show a modest response to ACTH through significant increases in cortisol production and steroidogenic enzyme expression [52]. Compared to NCIH295 cells, HAC cell clones are monoclonal and may provide a more stable steroidogenic phenotype [52]. Oki et al. investigated the responsiveness of HAC15 cell line to Ang II, and reported that aldosterone levels were elevated 3.6-fold by treatment with Ang II (10 nM) for 24 h [53]. The HAC15 cell line has been demonstrated to express StAR and various kinds of steroidogenic enzymes, including CYP11A1, CYP17, CYP21, HSD3B2, CYP11B1, and CYP11B2. Ang II treatment increased the expression levels of StAR, HSD3B2, CYP11B1, and CYP11B2 by 2.4-, 1.9-, 6.9-, and 7.9-fold, respectively, in this cell line, compared to H295R cells [53]. In addition, this cell line has been reported to be responsive to Ang III and metabolites of Ang II [53]. Of particular interest, aldosterone secretion was decreased by losartan alone, among the ATIII blockers employed [53]. HAC15 cell line was also found to be stimulated by both Ang II and III; both were reported to bind to AT1 receptors and to stimulate acute aldosterone synthesis. Synthesis of not just aldosterone, but also cortisol, was reported to be induced by Ang II, ACTH, or forskolin in HAC15 cell line [51,53]. Wang et al. compared CYP11B2 mRNA levels and aldosterone production in human adrenocortical cell lines [54]. qRT-PCR analysis showed that the NCI-H295 cell line had higher expression levels of CYP11B2. In the NCI-295 cell line, mRNA expression of CYP11B2 was almost two-fold compared to that was observed in the HAC 15 cell line [54]. However, aldosterone production was lower than in other cell lines, including the HAC 15 cell line, because of the lower expression of HSD3B2 observed in the NCIH295 cell line [54]. 6. Summary and future perspectives In this review, we have summarized the expression of various factors and regulators involved in adrenal aldosterone production in human adrenal tissues. In future, genomic and epigenomic
Please cite this article in press as: Y. Nakamura, et al., Aldosterone biosynthesis in the human adrenal cortex and associated disorders, J. Steroid Biochem. Mol. Biol. (2015), http://dx.doi.org/10.1016/j.jsbmb.2015.05.008
G Model SBMB 4418 No. of Pages 6
Y. Nakamura et al. / Journal of Steroid Biochemistry & Molecular Biology xxx (2015) xxx–xxx
regulators associated with aldosterone synthesis should be explored. In addition, the adrenocortical cell lines discussed above are far from ideal in vitro models of APA. Therefore, new in vitro models of aldosterone-producing tumors should also be explored in future studies. References [1] A. Splat, L. Hunyay, Control of aldosterone secretion: a model for convergence in cellular signaling pathways, Physiol. Rev. 84 (2004) 489–539. [2] J.R. Sowers, A. Whaley-Connell, M. Epstein, Narrative review: the emerging clinical implications of the role of aldosterone in the metabolic syndrome and resistant hypertension, Ann. Intern. Med. 150 (2009) 776–783. [3] M. Bochud, J. Nussberger, P. Bovet, M.R. Maillard, R.C. Elston, F. Paccaud, C. Shamlaye, M. Burnier, Plasma aldosterone is independently associated with the metabolic syndrome, Hypertension 48 (2006) 239–245. [4] J.W. Funder, Medicine. The genetics of primary aldosteronism, Science 331 (2011) 685–686. [5] G.P. Rossi, G. Bernini, C. Caliumi, G. Desideri, B. Fabris, C. Ferri, C. Ganzaroli, G. Giacchetti, C. Letizia, M. Maccario, F. Mallamaci, M. Mannelli, M.J. Mattarello, A. Moretti, G. Palumbo, G. Parenti, E. Porteri, A. Semplicini, D. Rizzoni, E. Rossi, M. Boscaro, A.C. Pessina, F. Mantero, P.S. Investigators, A prospective study of the prevalence of primary aldosteronism in 1125 hypertensive patients, J. Am. Coll. Cardiol. 48 (2006) 2293–2300. [6] J.S. Williams, G.H. Williams, A. Raji, X. Jeunemaitre, N.J. Brown, P.N. Hopkins, P. R. Conlin, Prevalence of primary hyperaldosteronism in mild to moderate hypertension without hypokalaemia, J. Hum. Hypertens. 20 (2006) 129–136. [7] P. Milliez, X. Girerd, P.F. Plouin, J. Blacher, M.E. Safar, J.J. Mourad, Evidence for an increased rate of cardiovascular events in patients with primary aldosteronism, J. Am. Coll. Cardiol. 45 (2005) 1243–1248. [8] A.M. Neville, M.J. O’Hare, Functional activity of the adrenal cortex, The Human Adrenal Cortex, Springer-Verlag, New York, 1982, pp. 68–98. [9] C.E. Gomez-Sanchez, X. Qi, C. Velarde-Miranda, M.W. Plonczynski, C.R. Parker, W. Rainey, F. Satoh, T. Maekawa, Y. Nakamura, H. Sasano, E.P. Gomez-Sanchez, Development of monoclonal antibodies against human CYP11B1 and CYP11B2, Mol. Cell. Endocrinol. 383 (2014) 111–117. [10] S. Mesiano, C.L. Coulter, R.B. Jaffe, Localization of cytochrome P450 cholesterol side-chain cleavage, cytochrome P450 17a-hydroxylase/17,20-lyase, and 3bhydroxysteroid dehydrogenase isomerase steroidogenic enzymes in human and rhesus monkey fetal adrenal glands: reappraisal of functional zonation, J. Clin. Endocrinol. Metab. 77 (1993) 1184–1189. [11] P.C. Coulter, S. Goldsmith, C.C. Mesiano, M.C. Voytek, J.I. Martin, Functional maturation of the primate fetal adrenal in vivo: 2. Ontogeny of corticosteroid synthesis is dependent upon specific zonal expression of 3b-hydroxysteroid dehydrogenase/isomerase (3bHSD), Endocrinology 137 (1996) 4953–4959. [12] S. Mesiano, R.B. Jaffe, Developmental and functional biology of the primate fetal adrenal cortex, Endocr. Rev. 18 (1997) 378–403. [13] M. Serón-Ferré, C.C. Lawrence, P.K. Siiteri, R.B. Jaffe, Steroid production by the definitive and fetal zones of the human fetal adrenal gland, J. Clin. Endocrinol. Metab. 47 (1978) 603–609. [14] H.P. Nelson, R.W. Kuhn, M.E. Deyman, R.B. Jaffe, Human fetal adrenal definitive and fetal zone metabolism of pregnenolone and corticosterone: alternate biosynthetic pathways and absence of detectable aldosterone synthesis, J. Clin. Endocrinol. Metab. 70 (1990) 693–698. [15] C.L. Coulter, R.B. Jaffe, Functional maturation of the primate fetal adrenal in vivo: 3. Specific zonal localization and developmental regulation of CYP21A2 (P421) and CYP11B1/CYP11B2 (P411/aldosterone synthase) lead to integrated concept of zonal and temporal steroid biosynthesis, Endocrinology 139 (1998) 5144–5150. [16] F. Bayard, I.G. Ances, A.J. Tapper, V.V. Weldon, A. Kowarski, C.J. Migeon, Transplacental passage and fetal secretion of aldosterone, J. Clin. Invest. 49 (1970) 1389–1393. [17] M. Serón-Ferré, E.G. Biglieri, R.B. Jaffe, Regulation of mineralocorticoid secretion by the superfused fetal monkey adrenal gland: lack of stimulation of aldosterone by ACTH, J. Dev. Physiol. 13 (1990) 33–36. [18] L. Breault, J.G. Lehoux, N. Gallo-Payet, The angiotensin AT2 receptor is present in the human fetal adrenal gland throughout the second trimester of gestation, J. Clin. Endocrinol. Metab. 81 (1996) 3914–3922. [19] A.J. Harper, J.E. Buster, P.R. Casson, Changes in adrenocortical function with aging and therapeutic implications, Semin. Reprod. Endocrinol. 17 (1999) 327– 338. [20] M. Aiba, M. Fujibayashi, Alteration of subcapsular adrenocortical zonation in humans with aging: the progenitor zone predominates over the previously well-developed zona glomerulosa after 40 years of age, J. Histochem. Cytochem. 59 (2011) 557–564. [21] M.H. Bassett, B. Mayhew, K. Rehman, P.C. White, F. Mantero, G. Arnaldi, P.M. Stewart, I. Bujalska, W.E. Rainey, Expression profiles for steroidogenic enzymes in adrenocortical disease, J. Clin. Endocrinol. Metab. 90 (2005) 5446–5455. [22] Y. Nakamura, T. Maekawa, S.J. Felizola, F. Satoh, X. Qi, C. Velarde-Miranda, M.W. Plonczynski, K. Ise, K. Kikuchi, W.E. Rainey, E.P. Gomez-Sanchez, C.E. GomezSanchez, H. Sasano, Adrenal CYP11B1/2 expression in primary aldosteronism: immunohistochemical analysis using novel monoclonal antibodies, Mol. Cell. Endocrinol. 392 (2014) 73–79.
5
[23] S. Konosu-Fukaya, Y. Nakamura, F. Satoh, S.J. Felizola, T. Maekawa, Y. Ono, R. Morimoto, K. Ise, K.I. Takeda, K. Katsu, F. Fujishima, A. Kasajima, M. Watanabe, Y. Arai, E.P. Gomez-Sanchez, C.E. Gomez-Sanchez, M. Doi, H. Okamura, H. Sasano, 3Beta-hydroxysteroid dehydrogenase isoforms in human aldosteroneproducing adenoma, Mol. Cell. Endocrinol. (2015) , doi:http://dx.doi.org/ 10.1016/j.mce.2014.10.008. [24] F. Fallo, C. Bertello, D. Tizzani, A. Fassina, S. Boulkroun, N. Sonino, S. Monticone, A. Viola, F. Veglio, P. Mulatero, Concurrent primary aldosteronism and subclinical cortisol hypersecretion: a prospective study, J. Hypertens. 29 (2011) 1773–1777. [25] K. Hiraishi, T. Yoshimoto, K. Tsuchiya, I. Minami, M. Doi, H. Izumiyama, H. Sasano, Y. Hirata, Clinicopathological features of primary aldosteronism associated with subclinical Cushing’s syndrome, Endocr. J. 58 (2011) 543–551. [26] K. Nanba, M. Tsuiki, K. Sawai, K. Mukai, K. Nishimoto, T. Usui, T. Tagami, H. Okuno, T. Yamamoto, A. Shimatsu, T. Katabami, A. Okumura, G. Kawa, A. Tanabe, M. Naruse, Histopathological diagnosis of primary aldosteronism using CYP11B2 immunohistochemistry, J. Clin. Endocrinol. Metab. 98 (2013) 1567–1574. [27] H. Sasano, Localization of steroidogenic enzymes in adrenal cortex and its disorders, Endocr. J. 41 (1994) 471–482. [28] E.A. Azizan, B.Y. Lam, S.J. Newhouse, J. Zhou, R.E. Kuc, J. Clarke, L. Happerfield, A. Marker, G.J. Hoffman, M.J. Brown, Microarray, qPCR, and KCNJ5 sequencing of aldosterone-producing adenomas reveal differences in genotype and phenotype between zona glomerulosa- and zona fasciculata-like tumors, J. Clin. Endocrinol. Metab. 97 (2012) E819–E829. [29] J. Simard, M.L. Ricketts, S. Gingras, P. Soucy, F.A. Feltus, M.H. Melner, Molecular biology of the 3beta-hydroxysteroid dehydrogenase/delta5–delta4 isomerase gene family, Endocr. Rev. 26 (2005) 525–582. [30] M. Doi, F. Satoh, T. Maekawa, Y. Nakamura, J.M. Fustin, M. Tainaka, Y. Hotta, Y. Takahashi, R. Morimoto, K. Takase, S. Ito, H. Sasano, H. Okamura, Isoformspecific monoclonal antibodies against 3beta-hydroxysteroid dehydrogenase/ isomerase family provide markers for subclassification of human primary aldosteronism, J. Clin. Endocrinol. Metab. 99 (2014) E257–E262. [31] T. Wang, F. Satoh, R. Morimoto, Y. Nakamura, H. Sasano, R.J. Auchus, M.A. Edwards, W.E. Rainey, Gene expression profiles in aldosterone-producing adenomas and adjacent adrenal glands, Eur. J. Endocrinol. 164 (2011) 613–619. [32] F. Beuschlein, S. Boulkroun, A. Osswald, T. Wieland, H.N. Nielsen, U.D. Lichtenauer, D. Penton, V.R. Schack, L. Amar, E. Fischer, A. Walther, P. Tauber, T. Schwarzmayr, S. Diener, E. Graf, B. Allolio, B. Samson-Couterie, A. Benecke, M. Quinkler, F. Fallo, P.F. Plouin, F. Mantero, T. Meitinger, P. Mulatero, X. Jeunemaitre, R. Warth, B. Vilsen, M.C. Zennaro, T.M. Strom, M. Reincke, Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary hypertension, Nat. Genet. 45 (2013) 440–444 (444e441-442). [33] S. Boulkroun, J.F. Golib Dzib, B. Samson-Couterie, F.L. Rosa, A.J. Rickard, T. Meatchi, L. Amar, A. Benecke, M.C. Zennaro, KCNJ5 mutations in aldosterone producing adenoma and relationship with adrenal cortex remodeling, Mol. Cell. Endocrinol. 371 (2013) 221–227. [34] T.A. Williams, S. Monticone, V.R. Schack, J. Stindl, J. Burrello, F. Buffolo, L. Annaratone, I. Castellano, F. Beuschlein, M. Reincke, B. Lucatello, V. Ronconi, F. Fallo, G. Bernini, M. Maccario, G. Giacchetti, F. Veglio, R. Warth, B. Vilsen, P. Mulatero, Somatic ATP1A1, ATP2B3, and KCNJ5 mutations in aldosteroneproducing adenomas, Hypertension 63 (2014) 188–195. [35] M.H. Bassett, P.C. White, W.E. Rainey, The regulation of aldosterone synthase expression, Mol. Cell. Endocrinol. 217 (2004) 67–74. [36] A.F. Gazdar, H.K. Oie, C.H. Shackleton, T.J. Chen, C.E. Myers, G.P. Chrousos, M.F. Brennan, C.A. Stein, R.V. La Rocca, Establishment and characterization of a human adrenocortical carcinoma cell line that expresses multiple pathways of steroid biosynthesis, Cancer Res. 50 (1990) 5488–5496. [37] W.E. Rainey, K. Sanera, B.P. Schimmer, Adrenocortical cell lines, Mol. Cell. Endocrinol. 228 (2004) 23–38. [38] B. Staels, D.W. Hum, W.L. Miller, Regulation of steroidogenesis in NCIH295 cells: a cellular model of the human fetal adrenal, Mol. Endocrinol. 7 (1993) 423–433. [39] P.J. Hornsby, J.M. McAllister, Culturing steroidogenic cells, Methods Enzymol. 206 (1991) 371–380. [40] I.M. Bird, N.A. Hanley, R.A. Word, J.M. Mathis, J.L. McCarthy, J.I. Mason, W.E. Rainey, Human NCI-H295 adrenocortical carcinoma cells: a model for angiotensin-II-responsive aldosterone secretion, Endocrinology 133 (1993) 1555–1561. [41] I.M. Bird, J.I. Mason, W.E. Rainey, Regulation of type 1 angiotensin II receptor messenger ribonucleic acid expression in human adrenocortical carcinoma H295 cells, Endocrinology 134 (1994) 2468–2474. [42] T. Ota, M. Doi, F. Yamazaki, D. Yarimizu, K. Okada, I. Murai, H. Hayashi, S. Kunisue, Y. Nakagawa, H. Okamura, Angiotensin II triggers expression of the adrenal gland zona glomerulosa-specific 3b-hydroxysteroid dehydrogenase isoenzyme through de novo protein synthesis of the orphan nuclear receptors NGFIB and NURR1, Mol. Cell. Biol. 34 (2014) 3880–3894. [43] K. Denner, W.E. Rainey, V. Pezzi, I.M. Bird, R. Bernhardt, J.M. Mathis, Differential regulation of 11 beta-hydroxylase and aldosterone synthase in human adrenocortical H295R cells, Mol. Cell. Endocrinol. 121 (1996) 87–91. [44] O.B. Holland, J.M. Mathis, I.M. Bird, W.E. Rainey, Angiotensin increases aldosterone synthase mRNA levels in human NCI-H295 cells, Mol. Cell. Endocrinol. 94 (1993) 9–13. [45] I.M. Bird, J.M. Mathis, J.I. Mason, W.E. Rainey, Ca(2+)-regulated expression of steroid hydroxylases in H295R human adrenocortical cells, Endocrinology 136 (1995) 5677–5684.
Please cite this article in press as: Y. Nakamura, et al., Aldosterone biosynthesis in the human adrenal cortex and associated disorders, J. Steroid Biochem. Mol. Biol. (2015), http://dx.doi.org/10.1016/j.jsbmb.2015.05.008
G Model SBMB 4418 No. of Pages 6
6
Y. Nakamura et al. / Journal of Steroid Biochemistry & Molecular Biology xxx (2015) xxx–xxx
[46] N.A. Hanley, R.M. Wester, B.R. Carr, W.E. Rainey, Parathyroid hormone and parathyroid hormone-related peptide stimulate aldosterone production in the human adrenocortical cell line, NCI-H295, Endocr. J. 1 (1993) 447–450. [47] E.F. Nogueira, C.A. Vargas, M. Otis, N. Gallo-Payet, W.B. Bollag, W.E. Rainey, Angiotensin-II acute regulation of rapid response genes in human, bovine, and rat adrenocortical cells, J. Mol. Endocrinol. 39 (2007) 365–374. [48] H.C. Hsu, T. Zhou, J.D. Mountz, Nur77 family of nuclear hormone receptors, Curr. Drug Targets Inflamm. Allergy 3 (2004) 413–423. [49] M.H. Bassett, P.C. White, W.E. Rainey, A role for the NGFI-B family in adrenal zonation and adrenocortical disease, Endocr. Res. 30 (2004) 567–574. [50] D.G. Romero, M. Plonczynski, G.R. Vergara, E.P. Gomez-Sanchez, C.E. GomezSanchez, Angiotensin II early regulated genes in H295R human adrenocortical cells, Physiol. Genomics 19 (2004) 106–116.
[51] J. Parmar, R.E. Key, W.E. Rainey, Development of an adrenocorticotropinresponsive human adrenocortical carcinoma cell line, J. Clin. Endocrinol. Metab. 93 (2008) 4542–4546. [52] T. Wang, W.E. Rainey, Human adrenocortical carcinoma cell lines, Mol. Cell. Endocrinol. 351 (2012) 58–65. [53 K. Oki, P.G. Kopf, W.B. Campbel, M.L. l Lam, T. Yamazaki, C.E. Gomez-Sanchez, E. P. Gomez-Sanchez, Angiotensin II and III metabolism and effects on steroid production in the HAC15 human adrenocortical cell line, Endocrinology 154 (2013) 214–221. [54] T. Wang, J.G. Rowland, J. Parmer, M. Nesterova, T. Seki, W.E. Rainey, Comparison of aldosterone production among human adrenocortical cell lines, Horm. Metab. Res. 44 (2012) 245–250.
Please cite this article in press as: Y. Nakamura, et al., Aldosterone biosynthesis in the human adrenal cortex and associated disorders, J. Steroid Biochem. Mol. Biol. (2015), http://dx.doi.org/10.1016/j.jsbmb.2015.05.008