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. Author manuscript; available in PMC: 2013 Aug 27.
Published in final edited form as: Mol Cell Endocrinol. 2008 Sep 3;302(2):230–236. doi: 10.1016/j.mce.2008.08.024

Angiotensin II Regulation of Adrenocortical Gene Transcription

Edson F Nogueira 1, Wendy B Bollag 2,3, William E Rainey 1
PMCID: PMC3752678  NIHMSID: NIHMS481905  PMID: 18812209

Abstract

Angiotensin II (Ang II) is the key peptide hormone in the renin-angiotensin-aldosterone system (RAAS). Its ability to regulate levels of circulating aldosterone relies on actions on adrenal glomerulosa cells. Many of the Ang II effects on glomerulosa cells involve a precisely coordinated regulation of signaling cascades and gene expression. The development of genome-wide gene arrays has allowed the definition of transcriptome-wide effects of Ang II in adrenocortical cells. Analysis of the Ang II gene targets reveals broad effects on cellular gene expression, particularly the rapid induction of numerous transcription factors that may regulate long-term steroid metabolism and cell growth/proliferation. Herein we discuss the Ang II-induced genes in adrenocortical cells and review the progress in defining the role of these genes in zona glomerulosa function.

Keywords: angiotensin, microarray, aldosterone, signaling, transcription factors, adrenal

1. Introduction

The RAAS plays a very important role in regulating blood volume and systemic vascular resistance. Renin, primarily released by the kidneys, converts circulating angiotensinogen into angiotensin I, which is further converted to the potent octapeptide Ang II by angiotensin-converting enzyme (ACE). Ang II is a major player in blood pressure regulation. Ang II elevates blood pressure by direct vasoconstrictor action and also by increasing sodium retention and blood volume through stimulation of aldosterone production from the adrenal cortex (Weir and Dzau, 1999). Aldosterone biosynthesis is also physiologically regulated by adrenocorticotropin (ACTH) and potassium (K+) (Williams, 2005). In addition to salt and water regulation, aldosterone is linked to the pathogenesis of several conditions, including inflammation and cardiovascular remodeling (Brown, 2005; Marney and Brown, 2007; Mehta and Griendling, 2007; Brown, 2008). Thus, the mechanisms regulating aldosterone production have recently acquired additional importance due to the pathologic implications of inappropriate aldosterone secretion.

Ang II influences aldosterone production through its capacity to directly activate signaling pathways, many of which are coupled to the expression of genes that chronically control adrenal differentiation and cell growth (Spat and Hunyady, 2004). The two types of Ang II receptors, AT1R (type 1) and AT2R (type 2), were identified by selective ligands and characterized as seven transmembrane receptors by molecular cloning. The G protein-coupled AT1R is the primary receptor for Ang II-regulated aldosterone production (Hajnoczky et al., 1992; Tsuchida et al., 1998) (Fig. 1). In the human adrenal cortex there is only one type of the AT1R, and it is expressed at much higher levels in the glomerulosa (aldosterone-producing zone) than in the fasciculata (cortisol-producing zone) (Bergsma et al., 1992). In rodents there are two genes that encode two isoforms of AT1R (AT1AR and AT1BR). The AT1AR is found in both the glomerulosa and medulla while the AT1BR is found only in the adrenal glomerulosa (Burson et al., 1994; Gasc et al., 1994; Wakamiya et al., 1994). Adrenal glomerulosa expression of the AT1R is enhanced on a low-sodium diet, suggesting that Ang II has the ability to enhance expression of its own receptor and, as a result, increase chronic aldosterone production (Lehoux et al., 1994). The actions of Ang II on the adrenal glomerulosa are often divided into acute effects, which relate to the rapid induction of aldosterone production, and the chronic effects that relate to increasing the capacity to produce aldosterone through both enlargement of the glomerulosa and increased expression of enzymes needed for aldosterone synthesis. It is likely that both acute and chronic actions of Ang II relate to the activation of several signaling cascades through the AT1R (Fig. 1).

Fig. 1.

Fig. 1

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Schematic of Ang II-induced gene-transcription through AT1R in adrenocortical cells and its effects on adrenal glomerulosa function. Ang II binds to Ang II type 1 receptors (AT1R) activating phospholipase C (PLC) through G protein subunit q/11 (Gq/11), and also activating several other signaling molecules, including protein kinase C (PKC), calcium/calmodulin-dependent kinases (CaMK), mitogen-activated protein kinase kinase - extracellular signal-regulated kinase 1 and 2 (MEK1/2-ERK1/2), src-family kinases (SRC), ras/raf kinases (RAS/RAF), and Janus kinase (JAK)/signal transduction and activators of transcription (STAT). Ang II-activation of such wide variety of intracellular signaling pathways culminates with phosphorylation/activation of transcription factors, leading to subsequent modulation of gene transcription, and therefore to changes in cell function.

2. Ang II intracellular signaling

Activation of AT1R, predominantly via Gq, stimulates phospholipases A2 (PLA2), C, and D, thereby activating protein kinase C (PKC) isoforms and inositol trisphosphate (IP3)/Ca2+ signaling (Bollag et al., 2002; Hunyady et al., 2004; Spat and Hunyady, 2004). G protein stimulation also leads to activation of mitogen-activated protein kinase pathways (MAPK), such as mitogen-activated protein kinase kinase - extracellular signal-regulated kinase 1 and 2 (MEK-ERK1/2), and calcium/calmodulin-dependent kinases (CaMK) (Chabre et al., 1995; Cote et al., 1998) (Fig. 1). Ang II can also act through G protein-independent pathways including β-arrestins, tyrosine kinases, and Janus kinase (JAK)/signal transduction and activators of transcription (STAT) pathways (Seta et al., 2002; Thomas and Qian, 2003; Wei et al., 2003; Miura et al., 2004). Studies in a variety of Ang II target cell types have shown that the Ang II activation of different pathways is time dependent. For example, activation of the G-protein-dependent pathway and generation of IP3 occurs in seconds, while MAPK and JAK/STAT activation occurs in minutes to hours after initial AT1R activation (Ishida et al., 1995; Schmitz et al., 1998). While many of the Ang II signaling cascades have been defined, an understanding of the downstream changes in gene expression has moved ahead very slowly, often through the definition of one gene-target at a time. Recent use of high-density microarray analysis has provided the methodology to define, in large numbers, the Ang II gene-targets in adrenocortical cell models. Over time these genes will be linked to function as well as the specific signaling pathway(s) that increase their expression.

3. Early Ang II response genes

It has long been known that adrenal cells in vitro and in vivo respond to Ang II treatment with the rapid induction of new gene expression (Viard et al., 1992b; Viard et al., 1992a; Viard et al., 1993). Several studies have recently made use of microarray analysis to identify a large numbers of transcripts that are acutely up-regulated following Ang II stimulation (Romero et al., 2004; Nogueira et al., 2007; Romero et al., 2007). Four adrenal model systems from three species have been used to define Ang II-responsive genes. We have defined a set of Ang II early response genes in primary cultures of rat and bovine glomerulosa cells as well in the human H295R adrenal cell line (Nogueira et al., 2007). In this study, adrenocortical cells were stimulated with Ang II followed by RNA isolation and analysis using species-specific microarrays. The microarrays used in this study covered a wide range of genes; approximately 40, 30, and 20 thousand independent genes from the human, rat, and bovine transcriptome, respectively. In comparison Romero et al., 2004 and 2007 used similar human and rat arrays for their study of H295R adrenal cells and freshly isolated rat glomerulosa cells (Romero et al., 2004; Romero et al., 2007). However, there were temporal differences between these studies that should be noted. We used a single 1 h Ang II-incubation with the goal of determining direct gene-targets that resulted from activation of cell signaling cascades. Romero et al. determined the Ang II-responsive genes following a 3 h treatment period of the H295R cell line and of freshly isolated rat glomerulosa cells. In addition, we used a concentration of 10 nM Ang II while Romero and colleagues used 100 nM Ang II. Based on data from these studies a view of the acute effects of Ang II on adrenal cell gene expression is now available.

Based on comparison of the microarray data from the cells in monolayer culture, there were a number of common genes that were increased with Ang II treatment. Interestingly eight of the most elevated transcripts were transcription factors. It is also interesting that, of the eight transcription factors, six had been shown, prior to microarray technology, to be increased in adrenocortical cells following Ang II-stimulation (Clark et al., 1992; Viard et al., 1992a; Enyeart et al., 1996; Fernandez et al., 2000). Two of the families of transcription factors, the activator protein 1 (AP-1) and nerve growth factor-induced B (NGFI-B) families, have been studied with regard to their expression and function within the adrenal cells (Table 1).

Table 1. Ang II-responsive genes in three glomerulosa cell models following 1 h of treatment.

Gene Name Gene Function Symbol Fold Change
Human adrenocortical cell line – H295R
Nuclear receptor subfamily 4, group A, member 2 Transcription factor NR4A2 30.9
v-106 FBJ murine osteosarcoma viral oncogene homolog Transcription factor FOS 25.4
FBJ murine osteosarc, viral oncogene homolog B Transcription Factor FOSB 15.5
Nuclear receptor subfamily 4, group A, member 3 Transcription Factor NR4A3 12.1
Early growth response 4 Transcription Factor EGR4 10.3
Early growth response 1 Transcription Factor EGR1 9.3
Cysteine-rich, anglogenic inducer, 61 Anglogenesic factor CYR51 7.7
Phosphoprotein regulated by mitogenic pathways Signal transducer TRIB1 7.6
Dual specificity phosphatase 1 (MKP-1) Protein phosphatase DUSP1 7.2
Early growth response 2 Transcription Factor EGR2 7.0
Bovine – primary adrenal glomerulosa cells
Nuclear receptor subfamily 4, group A, member 3 Transcription Factor NR4A3 27.4
Nuclear receptor subfamily 4, group A, member 2 Transcription Factor NR4A3 10.6
Murine FBU osteosarcoma viral (v-fos) oncogene homolog Transcription Factor FOS 8.1
Nuclear receptor subfamily 4, group A, member 1 Transcription Factor NR4A1 7.1
Highly similar to H. sapiens SNF1-like kinase (SNF1LK) Protein Kinase SNF1LK 6.2
Coagulation factor III (thromboplastin, tissue factor) Coagulation factor F3 5.1
Similar to DUSP-1 (MKP-1) Protein Phosphatase MKP-1 4.9
Steroldogenic accute regulatory protein Cholesterol transport STAR 4.2
Synaptonemal complex protein 3 Transcription Factor SYCP3 4.0
GDNF family receptor alpha 2 pre-pro-protein Receptor activity GFRA2 4.0
Rat – primary adrenal glomerulosa cells
Early growth response 3 Transcription Factor EGR3 24.7
FBJ murine osteosarcoma viral oncogene homolog B Transcription Factor FOSB 20.6
Nuclear receptor subfamily 4, group A, member 1 Transcription Factor NR4A1 16.0
Nuclear receptor subfamily 4, group A, member 3 Transcription Factor NR4A3 10.8
B-cell translocation gene 2 anti-proliferative Transcription Factor BTG2 5.6
Striated muscle activator of Rho-dependent signaling Signal transducer STARS 5.5
FBJ murine osteosarooma viral oncogene homolog Transcription Factor FOS 4.6
Nuclear receptor subfamily 4, group, member 2 Transcription Factor NR4A2 4.5
Corbon catabolite repression 4 protein homolog (noctumin) Transcription Factor CCR4 4.4
Inhibitor of DNA binding 4 Transcription repressor IDB4 3.8
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H295R cells were treated for 1 h followed by RNA isolation and microarray analysis. This table depicts the 10 genes with the highest fold induction at the end of treatment. Values represent the fold change as compared to untreated cells. (Nogueira et al., 2007)

Members of the NGFI-B family, including the nuclear receptor subfamily 4 group A member 1 (NR4A1), NR4A2, and NR4A3, have been shown to be highly expressed within the mouse, rat and human adrenal cortex (Wilson et al., 1993; Davis and Lau, 1994; Rainey et al., 2001). NR4A2 is primarily expressed in the adrenal glomerulosa, and in vitro studies suggest that it is a target for both Ang II and K+ treatment (Bassett et al., 2004b; Romero et al., 2004). NR4A1 is expressed in both the rat and human adrenal glomerulosa and fasciculata and is a target-gene for both Ang II and ACTH signaling (Bassett et al., 2004a; Lu et al., 2004). Both NR4A1 and NR4A2 can increase transcription of three genes that encode the enzymes responsible for the last steps in aldosterone synthesis: HSD3B2 (3beta-hydroxysteroid dehydrogenase type 2), CYP21 (21-hydroxylase), and CYP11B2 (aldosterone synthase) (Wilson et al., 1993; Bassett et al., 2004c; Bassett et al., 2004b; Kelly et al., 2004). Thus the NGFI-B family likely plays an important role in the expression of the enzymes needed for production of both mineralocorticoids and glucocorticoids.

Ang II also enhances expression of the members of the AP-1 complex [v-fos FBJ murine osteosarcoma viral oncogene homolog (FOS), FBJ murine osteosarcoma viral oncogene homolog B (FOSB), jun B proto-oncogene (JUNB), and v-jun sarcoma virus 17 oncogene homolog (JUN)]. These genes have long been recognized as Ang II target genes in bovine, rat and human adrenocortical cells (Viard et al., 1992b; Vinson et al., 1998; Romero et al., 2004; Nogueira et al., 2007). Adrenal cell induction of the AP-1 proteins is regulated, not only by Ang II, but also by ACTH, basic fibroblast growth factor (b-FGF), insulin-like growth factor (IGF-I), and transforming growth factor beta (TGF-β) (Viard et al., 1993; Lehoux et al., 1998; Naville et al., 2001). AP-1 proteins increase the expression of 11-beta-hydroxylase (CYP11B1) in rat and human adrenocortical cells (Mukai et al., 1995; Romero et al., 2007). It should be noted that members of the AP-1 complex are able to homo- and hetero-dimerize, and the subunit composition of AP-1 can often influence its effects on the expression of particular genes (Mukai et al., 1998). Thus, the ratios of FOS, FOSB, JUNB and JUN may be important in determining the ultimate cellular phenotype. Indeed we find that FOS heterodimers with members of the JUN family can repress transcription of the 17alpha-hydroxylase (CYP17) expression (Rainey and Sirianni, 2007). This repression may help explain the absence of CYP17 in the human and bovine adrenal glomerulosa cells.

Four members of the early growth response (EGR) transcription factor family, including EGR-1, EGR-2, EGR3, and EGR-4 are increased by acute Ang II treatment in adrenocortical cells (Nogueira et al., 2007; Romero et al., 2007) (Table 1). Romero et al. demonstrated that CYP11B2 transcription was increased by EGR2, while CYP11B1 transcription was stimulated by both EGR1 and EGR2 in H295R adrenocortical cells (Romero et al., 2007). The expression of EGR-1 is induced by diverse signals that initiate growth and differentiation in PC-12 pheochromocytoma cell line (Cao et al., 1990), as well as in vascular smooth muscle cells (VSMC) (Zhu et al., 2007). Therefore, EGR family members may be involved in several aspects of the Ang II regulation of the adrenal cortex.

There are many non-transcription factor genes that are rapidly induced following Ang II treatment. Several have recently been studied, including RGS2, a regulator of G protein signaling, that is rapidly induced by Ang II in H295R cells. RGS2 decreases aldosterone synthesis, presumably by modulating G protein coupling of AT1R to downstream pathways through its ability to accelerate the GTPase activity of Gα subunits of heterotrimeric G proteins (Romero et al., 2006). RGS2 overexpression decreases CYP11B2 expression and aldosterone production without affecting cortisol secretion, suggesting that RGS2 levels are increased by Ang II as a negative feedback mechanism (Romero et al., 2006). Mitogen-activated protein kinase phosphatase-1 (MKP-1), also named dual-specificity phosphatase 1 (DUSP-1), appears to be another such negative feedback pathway that is increased following Ang II treatment. MKP-1 is an early response gene that dephosphorylates and inactivates ERK-1/2 and has been linked to an inhibitory effect on mineralocorticoid synthesis in the adrenal cortex (Casal et al., 2007).

Taken together, these results suggest that signaling molecules activated by Ang II and the AT1R rapidly stimulate transcription of genes that play diverse role in the adrenal cortex, including cell growth and proliferation, and regulation of steroid production. Thus, this early cascade of events that happens shortly after Ang II stimulation is likely involved in many of the chronic changes in gene expression.

4. Chronic Ang II response genes

The chronic effects of Ang II on the adrenal glomerulosa are indeed dramatic. Rats and mice on a low sodium diet respond with increased renin and Ang II, which drives the expansion of the adrenal glomerulosa and its capacity to produce aldosterone. Studies examining the chronic effects of Ang II on glomerulosa cell gene expression have been limited mainly to genes that are directly involved in the regulation and/or production of steroid hormones. However, we recently examined the effects of chronic treatment on H295R cells using microarray analysis (Table 2). Below we discuss both the recent transcriptome analysis as well as the studies examining selective genes involved in steroidogenesis.

Table 2. Ang II-responsive genes following treatment with H295R for 72 h.

Gene Name Gene Function Symbol Fold Change
Human adrenocortical cell line – H295R
Cytochrome P450, family 11, subfamily B, polypeptide 2 Catalytic activity CYP11B2 6.7
Scavenger recetor class B, member 1 Receptor activity SCARB1 6.0
Matastasis associated lung adenocarcinoma transcript 1 Non-coding sequence MALAT-1 4.7
Secretoglobin, family 1C, member 1 (RYD5) Steroid binding SCGB1C1 4.4
Secreted frizzled-related protein 1 Signal transducer SFRP1 4.3
Rho GTPase activating protein 1B Signal transducer ARHGAP18 4.0
Maternaaly expressed 3 Tumor suppressor MEG3 3.8
UPD-glucose ceramide glucosyltransferase Transferase activity UGCC 3.8
Chromobox homolog 3 (HP1 gamma homolog) Chromatin remodeling CBX3 3.6
Wiskott-Aldrich syndrome like GTPase regulator activity WASL 3.5
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H295R cells were treated for 72 h followed by RNA isolation and microarray analysis. This table depicts the 10 genes with the highest fold induction at the end of treatment. Values represent the fold change as compared to untreated cells

Importantly, Ang II is able to regulate transcription and membrane expression of its own receptor in adrenocortical cells. In vivo studies using rats provided a low sodium diet demonstrate that these animals increase adrenal expression of both AT1AR and AT1BR mRNA; and this effect is blocked by AT1R pharmacological blockage (Wang and Du, 1995; Du et al., 1996) and by ACE inhibitors (Lehoux et al., 1994; Wakamiya et al., 1994). In spontaneous hypertensive rats (SHR), which have increased RAAS activity, both ACE inhibition and a calcium channel blockade decrease AT1R mRNA in the adrenal gland (Kitami et al., 1992). Conversely, in human adrenal fasciculata/reticularis (inner zones of the adrenal cortex) cells, Ang II decreases expression and binding of AT1R (Naville et al., 1993); and similar effects are obtained using bovine adrenal glomerulosa cells (l'Allemand et al., 1996). In addition, in H295R cells, AT1R expression is rapidly decreased after treatment with Ang II (through PKC and Ca2+ signaling activation), K+ (through Ca2+ signaling activation) and forskolin/dibutyryl-cAMP (through activation of protein kinase A) (Bird et al., 1994; Bird et al., 1995a; Bird et al., 1995b). However this inhibitory effect decreases over time such that by 48 h of Ang II-treatment levels are similar to those in untreated cells (Bird et al., 1995a). The results of our microarray analysis of H295R cells treated with Ang II for 72 h agrees with this last study, and AT1R is not differentially expressed between treated and control samples after long-term Ang II incubation. Taken together the chronic effects of Ang II on its own receptor appear to differ depending on the models system. In vivo studies appear to support the ability of Ang II to up-regulate its expression, while cell culture studies do not show a chronic effect on AT1R mRNA or binding.

Glomerulosa cells like all steroid producing cells produce steroid using cholesterol as precursor. Adrenocortical cells produce steroids from both cholesterol synthesized de novo and that taken up from the circulation bound to HDL via the scavenger receptor B type I (SR-BI) and to LDL via the LDL receptor pathway (Gwynne et al., 1976; Rainey et al., 1992; Cherradi et al., 2003; Pilon et al., 2003). Ang II has been shown to up-regulate expression of both of these receptors (Pilon et al., 2003). Interestingly, the increased transcription of genes involved in the regulation of cholesterol uptake by adrenocortical cells, such as low density lipoprotein receptor-related protein binding protein (LRP2PB) occurs shortly after Ang II-stimulation (Nogueira et al., 2007). After a longer Ang II incubation, additional cholesterol synthesis/uptake genes, such as 3-hydroxy-3-methylglutaryl-coenzyme A synthase 1 (HMGCS1), mevalonate kinase (MVK), CCAAT/enhancer-binding protein (C/EPB), and scavenger receptor class B, member 1 (SCARB1) are up-regulated (Liang et al., 2007). The next step in steroidogenesis, the transport of cholesterol into the mitochondria by StAR protein, has also been demonstrated to be up-regulated by Ang II stimulation in a number of studies (Clark et al., 1995; Cherradi et al., 1998). Microarray analysis of primary bovine adrenal glomerulosa cells shows that up-regulation of StAR is initiated as early as 1 h after Ang II stimulation, while in human H295R cells StAR levels (mRNA and protein) are significantly elevated only after a 6 h incubation with Ang II (Clark et al., 1995).

Part of the chronic response of glomerulosa cells to activation of the RAAS is to increase the capacity to produce aldosterone. To that end, Ang II also regulates the expression of the enzymes responsible for aldosterone and cortisol production, namely: cholesterol side-chain cleavage (CYP11A1), HSD3B2, CYP21, CYP11B1 (the last step in cortisol biosynthesis), and CYP11B2 (Rainey et al., 1991; Tremblay et al., 1992; Adler et al., 1993; Holland and Carr, 1993; Bird et al., 1998; Spat and Hunyady, 2004). Not all steroidogenic enzymes increase in response to Ang II. Several reports using bovine, sheep and human adrenal cell cultures document the ability of Ang II through PKC signaling to decrease expression of CYP17 (Naseeruddin and Hornsby, 1990; Rainey et al., 1991; Bird et al., 1992; Bird et al., 1996). This agrees with the fact that CYP17 is not present in the glomerulosa of adrenals from cortisol secreting species. Our microarray analysis of H295R cells treated for 72 h with Ang II demonstrates changes is several of the gene mentioned above including CYP11B2 as the most up-regulated gene, followed by other genes involved in cholesterol update and metabolism such as the HDL receptor SCARB1 and a steroid binding protein SCGB1C1 (Table 2). Thus, Ang II chronically increases the capacity for steroidogenesis by increasing cholesterol update and synthesis as well as increasing steroid biosynthetic enzymes.

Contrasting with the presence of more than three hundred up-regulated transcription factors in the 1 h study, 72 h of Ang II treatment only increased 5 transcription factors, namely: paternally expressed 3(PEG3), estrogen-related receptor gamma (ERRG), RAR-related orphan receptor A (RORA), ocular development-associated gene (ODAG), transcriptional coactivator tubedown-100 (TDBN100). PEG3 expression has been described to activate tumor necrosis factor (TNF)/ nuclear factorkappaB (NF-κB) pathway in human embryonic kidney cells, and therefore may participate in cell proliferation and differentiation, although the function of PEG3, as well as ERRG, ODAG, RORA, and TDBN100 in the adrenal cortex has not been described.

In addition to the chronic effects on secretion of aldosterone, Ang II also stimulates proliferation of adrenocortical cells in vivo (Tian et al., 1995; McEwan et al., 1999) and primary bovine adrenal glomerulosa cells in vitro (Tian et al., 1995), although rat adrenal glomerulosa cells in vitro exhibit Ang II-elicited hypertrophy rather than proliferation (Otis et al., 2008). The mitogenic effects of Ang II in adrenocortical cells have also been shown in terms of the Ang II-induced induction of the expression of cyclin D1 (Watanabe et al., 1996), an important molecule involved in the G1 phase progression of the cell cycle. This increase has been shown to be partially mediated by EGR1 (Guillemot et al., 2001) which is one of the Ang II rapid response genes (Table 1). Ang II exerts proliferating and hypertrophic effects in other targets, including epithelial cells, VSMC, fibroblasts and cardiomyocytes. While expansion of the adrenal glomerulosa is part of the physiologic mechanisms of increasing aldosterone biosynthesis, chronic effects of Ang II on cell growth and deposition of extracellular matrix under pathological conditions ultimately can lead to vascular dysfunction and cardiac insufficiency.

5. Conclusions

Microarray analysis and real-time RT-PCR have become common-place in the examination of gene expression. Using adrenocortical cells, we have shown that large numbers of genes are increased within a short time of Ang II stimulation; followed by a group of genes that continue to show differences in expression days later. Acutely, Ang II increases the expression of hundreds of genes, most of which have not been studied with regard to adrenal function. Previous research has focused on the role of several transcription factors, including the NGFI-B family that appear to increase expression of the enzymes involved in aldosterone biosynthesis. However, at present, the numbers of Ang II response genes that have not been studied far outnumber the genes which have been examined. Therefore, further characterization of the Ang II activated signaling cascades and their association with specific gene induction is needed and should provide a clearer understanding of how Ang II regulates adrenocortical aldosterone production.

Acknowledgments

This research was supported by National Institute of Health grant DK43140 to WE Rainey, and HL70046 to WBB. The authors declare that there is no conflict of interest that would prejudice the impartiality of this scientific work.

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