Regulation Of Aldosterone Synthesis Research Articles

Primary aldosteronism and pregnancy

The article is devoted to a review of scientific publications that study primary aldosteronism (PA), as well as its features during pregnancy. PA is the most common cause of secondary hypertension. There are few data on PA during pregnancy. PA is characterized by excessive production of aldosterone, which leads to hemodynamic changes in the body, especially the appearance of hypertension. Studies in recent years have shown that up to 88% of adenomas may have gene mutations involved in the regulation of aldosterone synthesis: KCNJ5, CACNA1D, ATP1A1, ATP2B3 and CTNNB1. PA is a renin-independent hypersecretion of aldosterone, which remains an underdiagnosed cause of hypertension. Early diagnosis and treatment contribute to the favorable course of this disease.Changes in renin-angiotensin-aldosterone activity during pregnancy may delay diagnosis. The risk of combined preeclampsia in patients diagnosed with PA may be even higher than in women with chronic primary hypertension with an estimated risk of approximately 17–25%. Given the lack of treatment standards, the management of pregnancies described in scientific publications is different.However, given current knowledge, the following recommendations are possible:• pregnancy should be programmed, and PA should be monitored as much as possible without the use of spironolactone before pregnancy;• adrenalectomy should be performed if unilateral adrenal damage is found before pregnancy;• antihypertensive drugs approved for use during pregnancy, such as methyldopa, β-blockers, should be used during pregnancy planning;• spironolactone should be discontinued before conception.It can be used a diuretic that was prescribed before pregnancy, or prescribed the diuretic in a situation of uncontrolled hypertension.The article also presents our own clinical case of three pregnancies in one woman with PA, their course and outcome. Only the first pregnancy was complicated by preeclampsia, and PA was diagnosed 5 years after the first birth. All pregnancies ended with the birth of living, full-term babies.

Hormonal Mechanisms in Essential Hypertension

Abstract “Essential” hypertension is related to multiple mechanisms that affect cardiac output and peripheral resistance and is a consequence of the interaction between external factors and genetic factors. Neuro-hormonal factors are essential in the pathophysiology of hypertension and among them the renin-angiotensin-aldosterone system (RAAS) has a main role in the physiological and pathological response of the cardiovascular system. RAAS functions as an endocrine system, but also has paracrine and autocrine functions in many tissues and organs. RAAS regulates extracellular fluid volume and peripheral resistance via systemic and local actions in various tissues. RAAS also participates in endothelial dysfunction, inflammation and vascular fibrosis, cardiac fibrosis and cardiovascular remodelling, with worsening hypertension and target organ injury. Aldosterone is involved in “essential” hypertension via discrete variations in the regulation of aldosterone synthesis in the absence of confirmed primary hyperaldosteronism. A complete evaluation of these systems is needed for a thorough understanding of hypertension.

Effect of Dietary Sodium Modulation on Pig Adrenal Steroidogenesis and Transcriptome Profiles.

Primary aldosteronism is a frequent form of endocrine hypertension caused by aldosterone overproduction from the adrenal cortex. Regulation of aldosterone biosynthesis has been studied in rodents despite differences in adrenal physiology with humans. We, therefore, investigated pig adrenal steroidogenesis, morphology, and transcriptome profiles of the zona glomerulosa (zG) and zona fasciculata in response to activation of the renin-angiotensin-aldosterone system by dietary sodium restriction. Six-week-old pigs were fed a low- or high-sodium diet for 14 days (3 pigs per group, 0.4 g sodium/kg feed versus 6.8 g sodium/kg). Plasma aldosterone concentrations displayed a 43-fold increase (P=0.011) after 14 days of sodium restriction (day 14 versus day 0). Low dietary sodium caused a 2-fold increase in thickness of the zG (P<0.001) and an almost 3-fold upregulation of CYP11B (P<0.05) compared with high dietary sodium. Strong immunostaining of the KCNJ5 (G protein-activated inward rectifier potassium channel 4), which is frequently mutated in primary aldosteronism, was demonstrated in the zG. mRNA sequencing transcriptome analysis identified significantly altered expression of genes modulated by the renin-angiotensin-aldosterone system in the zG (n=1172) and zona fasciculata (n=280). These genes included many with a known role in the regulation of aldosterone synthesis and adrenal function. The most highly enriched biological pathways in the zG were related to cholesterol biosynthesis, steroid metabolism, cell cycle, and potassium channels. This study provides mechanistic insights into the physiology and pathophysiology of aldosterone production in a species closely related to humans and shows the suitability of pigs as a translational animal model for human adrenal steroidogenesis.

Of channels and pumps: different ways to boost the aldosterone?

The mineralocorticoid aldosterone is a major factor controlling the salt and water balance and thereby also the arterial blood pressure. Accordingly, primary aldosteronism (PA) characterized by an inappropriately high aldosterone secretion is the most common form of secondary hypertension. The physiological stimulation of aldosterone synthesis in adrenocortical glomerulosa cells by angiotensin II and an increased plasma K+ concentration depends on a membrane depolarization and an increase in the cytosolic Ca2+ activity. Recurrent gain-of-function mutations of ion channels and transporters have been identified in a majority of cases of aldosterone-producing adenomas and in familial forms of PA. In this review, the physiological role of these genes in the regulation of aldosterone synthesis and the altered function of the mutant proteins as well are described. The specific changes of the membrane potential and the cellular ion homoeostasis in adrenal cells expressing the different mutants are compared, and their impact on autonomous aldosterone production and proliferation is discussed.

High potassium promotes mutual interaction between (pro)renin receptor and the local renin-angiotensin-aldosterone system in rat inner medullary collecting duct cells.

(Pro)renin receptor (PRR) is predominantly expressed in the collecting duct (CD) with unclear functional implication. It is not known whether CD PRR is regulated by high potassium (HK). Here, we aimed to investigate the effect of HK on PRR expression and its role in regulation of aldosterone synthesis and release in the CD. In primary rat inner medullary CD cells, HK augmented PRR expression and soluble PPR (sPRR) release in a time- and dose-dependent manner, which was attenuated by PRR small interfering RNA (siRNA), eplerenone, and losartan. HK upregulated aldosterone release in parallel with an increase of CYP11B2 (cytochrome P-450, family 11, subfamily B, polypeptide 2) protein expression and upregulation of medium renin activity, both of which were attenuated by a PRR antagonist PRO20, PRR siRNA, eplerenone, and losartan. Similarly, prorenin upregulated aldosterone release and CYP11B2 expression, both of which were attenuated by PRR siRNA. Interestingly, a recombinant sPRR (sPRR-His) also stimulated aldosterone release and CYP11B2 expression. Taken together, we conclude that HK enhances a local renin-angiotensin-aldosterone system (RAAS), leading to increased PRR expression, which in turn amplifies the response of the RAAS, ultimately contributing to heightened aldosterone release.

Adipocyte-Derived Hormone Leptin Is a Direct Regulator of Aldosterone Secretion, Which Promotes Endothelial Dysfunction and Cardiac Fibrosis.

In obesity, the excessive synthesis of aldosterone contributes to the development and progression of metabolic and cardiovascular dysfunctions. Obesity-induced hyperaldosteronism is independent of the known regulators of aldosterone secretion, but reliant on unidentified adipocyte-derived factors. We hypothesized that the adipokine leptin is a direct regulator of aldosterone synthase (CYP11B2) expression and aldosterone release and promotes cardiovascular dysfunction via aldosterone-dependent mechanisms. Immunostaining of human adrenal cross-sections and adrenocortical cells revealed that adrenocortical cells coexpress CYP11B2 and leptin receptors. Measurements of adrenal CYP11B2 expression and plasma aldosterone levels showed that increases in endogenous (obesity) or exogenous (infusion) leptin dose-dependently raised CYP11B2 expression and aldosterone without elevating plasma angiotensin II, potassium or corticosterone. Neither angiotensin II receptors blockade nor α and β adrenergic receptors inhibition blunted leptin-induced aldosterone secretion. Identical results were obtained in cultured adrenocortical cells. Enhanced leptin signaling elevated CYP11B2 expression and plasma aldosterone, whereas deficiency in leptin or leptin receptors blunted obesity-induced increases in CYP11B2 and aldosterone, ruling out a role for obesity per se. Leptin increased intracellular calcium, elevated calmodulin and calmodulin-kinase II expression, whereas calcium chelation blunted leptin-mediated increases in CYP11B2, in adrenocortical cells. Mineralocorticoid receptor blockade blunted leptin-induced endothelial dysfunction and increases in cardiac fibrotic markers. Leptin is a newly described regulator of aldosterone synthesis that acts directly on adrenal glomerulosa cells to increase CYP11B2 expression and enhance aldosterone production via calcium-dependent mechanisms. Furthermore, leptin-mediated aldosterone secretion contributes to cardiovascular disease by promoting endothelial dysfunction and the expression of profibrotic markers in the heart.

Regulation of aldosterone synthesis and secretion.

Aldosterone is a steroid hormone synthesized in and secreted from the outer layer of the adrenal cortex, the zona glomerulosa. Aldosterone is responsible for regulating sodium homeostasis, thereby helping to control blood volume and blood pressure. Insufficient aldosterone secretion can lead to hypotension and circulatory shock, particularly in infancy. On the other hand, excessive aldosterone levels, or those too high for sodium status, can cause hypertension and exacerbate the effects of high blood pressure on multiple organs, contributing to renal disease, stroke, visual loss, and congestive heart failure. Aldosterone is also thought to directly induce end-organ damage, including in the kidneys and heart. Because of the significance of aldosterone to the physiology and pathophysiology of the cardiovascular system, it is important to understand the regulation of its biosynthesis and secretion from the adrenal cortex. Herein, the mechanisms regulating aldosterone production in zona glomerulosa cells are discussed, with a particular emphasis on signaling pathways involved in the secretory response to the main controllers of aldosterone production, the renin-angiotensin II system, serum potassium levels and adrenocorticotrophic hormone. The signaling pathways involved include phospholipase C-mediated phosphoinositide hydrolysis, inositol 1,4,5-trisphosphate, cytosolic calcium levels, calcium influx pathways, calcium/calmodulin-dependent protein kinases, diacylglycerol, protein kinases C and D, 12-hydroxyeicostetraenoic acid, phospholipase D, mitogen-activated protein kinase pathways, tyrosine kinases, adenylate cyclase, and cAMP-dependent protein kinase. A complete understanding of the signaling events regulating aldosterone biosynthesis may allow the identification of novel targets for therapeutic interventions in hypertension, primary aldosteronism, congestive heart failure, renal disease, and other cardiovascular disorders.

PCP4: a regulator of aldosterone synthesis in human adrenocortical tissues

Purkinje cell protein 4 (PCP4) is a calmodulin (CaM)-binding protein that accelerates calcium association and dissociation with CaM. It has been previously detected in aldosterone-producing adenomas (APA), but details on its expression and function in adrenocortical tissues have remained unknown. Therefore, we performed the immunohistochemical analysis of PCP4 in the following tissues: normal adrenal (NA; n=15), APA (n=15), cortisol-producing adenomas (n=15), and idiopathic hyperaldosteronism cases (IHA; n=5). APA samples (n=45) were also submitted to quantitative RT-PCR of PCP4, CYP11B1, and CYP11B2, as well as DNA sequencing for KCNJ5 mutations. Transient transfection analysis using PCP4 siRNA was also performed in H295R adrenocortical carcinoma cells, following ELISA analysis, and CYP11B2 luciferase assays were also performed after PCP4 vector transfection in order to study the regulation of PCP4 protein expression. In our findings, PCP4 immunoreactivity was predominantly detected in APA and in the zona glomerulosa of NA and IHA. In APA, the mRNA levels of PCP4 were significantly correlated with those of CYP11B2 (P<0.0001) and were significantly higher in cases with KCNJ5 mutation than WT (P=0.005). Following PCP4 vector transfection, CYP11B2 luciferase reporter activity was significantly higher than controls in the presence of angiotensin-II. Knockdown of PCP4 resulted in a significant decrease in CYP11B2 mRNA levels (P=0.012) and aldosterone production (P=0.011). Our results indicate that PCP4 is a regulator of aldosterone production in normal, hyperplastic, and neoplastic human adrenocortical cells.

Abstract 280: Modulation of Aldosterone Synthesis in Human Adrenocortical Cells by Estrogens via an Interaction on Beta Estrogen and Gpr30 Receptor Subtypes

Background and aim. The gender dimorphism in the pressor effect of hyperaldosteronism suggests that estrogens may modulate aldosterone synthesis. Estrogens were suggested to affect adrenocortical cell proliferation via beta estrogen receptor (ERβ), but it remains unknown if they also influence aldosterone synthesis. Methods. We therefore investigated the expression of alpha (ERα), ERβ and of G protein-coupled receptor (GPR)30 in HAC15 cells, a human adrenocortical carcinoma cell line. HAC15 cells were stimulated with 10 -7 M 17β-estradiol (E2) alone, or with a selective ERβ antagonist (10 -5 M; Tetrahydrochrysenediol THC), a selective ERα antagonist (10 -5 M; MPP dihydrochloride), a non selective ERα and ERβ antagonist (10 -5 M; ICI 182.780 fulvestrant), a selective GPR30 receptor antagonist (10 -5 M; G-15). The cells were also exposed to the highly selective GPR30 agonist G-1, alone or in the presence of MPP, or THC, or Fulvestrant and G-15. CYP11B2 mRNA expression was measured with quantitative real time RT-PCR (Universal Probe Library Roche). Results. The three estrogen receptor subtypes were found to be expressed at different levels (ERβ&gt;&gt;ERα=GPR30) in HAC15 cells. E2 alone or on top of selective ERα antagonism did not alter CYP11B2 expression. At variance, E2 on top of selective ERβ antagonism, or of combined ERβ and ERα antagonism, caused a 5- to 7- fold upregulation of CYP11B2 mRNA, a finding that was replicated by the exposure of cells to G-1 on top of combined ERβ and ERα blockade. Conclusions . 1) GPR30 is expressed in human adrenocortical cells at levels that are comparable to ERα, but less abundatly than ERβ subtype receptor. 2) 17β-estradiol activates CYP11B2 synthesis via an interaction between ERβ blockade and GPR30 activation. Hence, by showing a role for estrogens in the regulation of aldosterone synthesis via GPR30 subtype receptor, these results could account for the diverse pressor effects of excess aldosterone in men and in fertile vs post-menopausal women.

Role of Intramitochondrial Arachidonic Acid and Acyl-CoA Synthetase 4 in Angiotensin II-Regulated Aldosterone Synthesis in NCI-H295R Adrenocortical Cell Line

Although the role of arachidonic acid (AA) in angiotensin II (ANG II)- and potassium-stimulated steroid production in zona glomerulosa cells is well documented, the mechanism responsible for AA release is not fully described. In this study we evaluated the mechanism involved in the release of intramitochondrial AA and its role in the regulation of aldosterone synthesis by ANG II in glomerulosa cells. We show that ANG II and potassium induce the expression of acyl-coenzyme A (CoA) thioesterase 2 and acyl-CoA synthetase 4, two enzymes involved in intramitochondrial AA generation/export system well characterized in other steroidogenic systems. We demonstrate that mitochondrial ATP is required for AA generation/export system, steroid production, and steroidogenic acute regulatory protein induction. We also demonstrate the role of protein tyrosine phosphatases regulating acyl-CoA synthetase 4 and steroidogenic acute regulatory protein induction, and hence ANG II-stimulated aldosterone synthesis.

A Lifetime of Aldosterone Excess: Long-Term Consequences of Altered Regulation of Aldosterone Production for Cardiovascular Function

Up to 15% of patients with essential hypertension have inappropriate regulation of aldosterone; although only a minority have distinct adrenal tumors, recent evidence shows that mineralocorticoid receptor activation contributes to the age-related blood pressure rise and illustrates the importance of aldosterone in determining cardiovascular risk. Aldosterone also has a major role in progression and outcome of ischemic heart disease. These data highlight the need to understand better the regulation of aldosterone synthesis and its action. Aldosterone effects are mediated mainly through classical nuclear receptors that alter gene transcription. In classic epithelial target tissues, signaling mechanisms are relatively well defined. However, aldosterone has major effects in nonepithelial tissues that include increased synthesis of proinflammatory molecules and reactive oxygen species; it remains unclear how these effects are controlled and how receptor specificity is maintained. Variation in aldosterone production reflects interaction of genetic and environmental factors. Although the environmental factors are well understood, the genetic control of aldosterone synthesis is still the subject of debate. Aldosterone synthase (encoded by the CYP11B2 gene) controls conversion of deoxycorticosterone to aldosterone. Polymorphic variation in CYP11B2 is associated with increased risk of hypertension, but the molecular mechanism that accounts for this is not known. Altered 11beta-hydroxylase efficiency (conversion of deoxycortisol to cortisol) as a consequence of variation in the neighboring gene (CYP11B1) may be important in contributing to altered control of aldosterone synthesis, so that the risk of hypertension may reflect a digenic effect, a concept that is discussed further. There is evidence that a long-term increase in aldosterone production from early life is determined by an interaction of genetic and environmental factors, leading to the eventual phenotypes of aldosterone-associated hypertension and cardiovascular damage in middle age and beyond. The importance of aldosterone has generated interest in its therapeutic modulation. Disadvantages associated with spironolactone (altered libido, gynecomastia) have led to a search for alternative mineralocorticoid receptor antagonists. Of these, eplerenone has been shown to reduce cardiovascular risk after myocardial infarction. The benefits and disadvantages of this therapeutic approach are discussed.

Teaching aldosterone regulation and basic scientific principles using a classic paper by Dr. James O. Davis and colleagues

Classroom discussion of scientific articles can be an effective means of teaching scientific principles and methodology to both undergraduate and graduate science students. The availability of classic papers from the American Physiological Society Legacy Project has made it possible to access articles dating back to the early portions of the 20th century. In this article, we discuss a classic paper from the laboratory of Dr. James O. Davis on the regulation of aldosterone synthesis from the adrenal zona glomerulosa cell. Dr. Davis has conducted much of the seminal research investigating the renin-angiotensin system and the regulation of aldosterone release by angiotensin II. In addition to a characterization of the effects of ACTH on aldosterone regulation, this study is useful for discussing the basic principles of negative feedback pathways of the hypothalamic-pituitary axis. This study also provides examples of early bioassay techniques for the detection of angiotensin II and of the importance of quantitative measurements when investigating physiological responses. Three figures and one table are reproduced from the original article along with a series of discussion questions designed to facilitate discovery learning.

Regulation of Aldosterone Synthesis by Adenosine A1 Receptors—Implication for Pathophysiology of Cardiac Hypertrophy and Dysfunction—

Regulation of Aldosterone Synthesis by Adenosine A1 Receptors—Implication for Pathophysiology of Cardiac Hypertrophy and Dysfunction—

Glomerulosa function and aldosterone synthesis in the rat

Since its discovery, it has been generally assumed that the primary function of the zona glomerulosa of the adrenal cortex is the secretion of aldosterone. Taking evidence from the rat, and recognising that there is probably considerable species variation, I argue here that the glomerulosa in fact has many functions, including aldosterone synthesis, but is probably only a relatively poor de novo source of steroid. In vitro, the CYP11B2 (aldosterone synthase) of the glomerulosa can and does utilise as substrates products arising from CYP11B1 (11β-hydroxylase) activity in fasciculata cells. Whether it does in vivo is open to question, but corticosterone and 18-hydroxydeoxycorticosterone are both present in circulating rat plasma at suitable concentrations. Such a mechanism would explain several inconsistencies in the literature, including the anomalous distribution of steroidogenic enzymes in the glomerulosa, the stimulation of CYP11B1 products by aldosterone secretagogues such as potassium ions or angiotensin II, the partial dependence of aldosterone secretion in vivo on an intact pituitary, the sensitivity of aldosterone secretion to tissue disruption in vitro, and the “late pathway” regulation of aldosterone synthesis.

Endothelial cell nitric oxide inhibits aldosterone synthesis in zona glomerulosa cells: modulation by oxygen.

The regulation of aldosterone synthesis by endogenous nitric oxide (NO) was examined in cultured cells of the adrenal cortex. Endothelial NO synthase (eNOS) was detected by Western blot in cultured adrenal endothelial cells (ECs) but not in zona glomerulosa (ZG) cells or adrenal fibroblasts. Neither inducible (iNOS) nor neuronal NOS (nNOS) isoforms were detected in the cells. Only ECs had NOS activity and converted [(3)H]L-arginine to [(3)H]L-citrulline. Angiotensin II (ANG II, 100 nM) increased EC production of nitrate/nitrite by 2.4-fold. Coincubation with ECs or treatment with DETA nonoate increased the fluorescence of ZG cells loaded with an NO-sensitive dye, diaminofluorescein 2 diacetate (DAF-2 DA). DETA nonoate inhibited ANG II (1 nM) and potassium (10 mM) -stimulated aldosterone release in a concentration-related manner. This inhibitory effect of NO was enhanced >10-fold by decreasing the oxygen concentration from 21 to 8%. Coincubation of EC and ZG cells in 8% oxygen inhibited ANG II-induced aldosterone release, and inhibition was reversed by blockade of NOS. These findings indicate that adrenal EC-derived NO inhibits aldosterone release by cultured ZG cells and that the sensitivity to NO inhibition is increased at low oxygen concentrations.

The role of nitric oxide in the regulation of aldosterone synthesis by adrenal glomerulosa cells.

The role of nitric oxide (NO) in the regulation of aldosterone synthesis in the adrenal glomerulosa is not known. In this study, we observed that liberators of NO such as S-nitroso-N-acetyl-penicillamine (SNAP), sodium nitroprusside (Snp) and spermine nonoate (SNO) could significantly inhibit angiotensin II (AII) and ACTH-induced aldosterone synthesis in isolated rat and cultured human adrenal glomerulosa cells. To evaluate more precisely whether glomerulosa cells express NO synthase, we performed immunoblotting experiments with antibodies specific for the endothelial type ecNO synthase as well as the neuronal NO synthase. This revealed the presence of the ecNO synthase in rat adrenal capsules, in normal and in adenomatous human adrenal glomerulosa tissue, as well as in freshly dispersed rat adrenal glomerulosa cells. Furthermore, on immunohistochemical analysis, rat adrenal glomerulosa cell sections showed strongly positive staining for ecNO synthase. These results suggest that NO may be an important negative modulator of adrenal glomerulosa steroidogenesis.

Regulation of aldosterone secretion

Although angiotensin II and potassium ion play the leading parts in the regulation of aldosterone synthesis and secretion, various factors have recently been shown to act in concert with these two secretagogues, such as neurotransmitters, neurohormones, the intra-adrenal renin-angiotensin system, antioxidant vitamins, and adrenomedullin. Extra-adrenal, vascular production of aldosterone has been proposed as an intriguing, regulated mechanism for the modulation of angiotensin II-induced trophic effects. Much attention has recently been devoted to the intracellular signaling mechanisms leading to both the acute and chronic stimulation of aldosterone biosynthesis: role of voltage-gated calcium channels, of protein phosphorylation by various kinases, regulation of intramitochondrial cholesterol transport, and control of expression of aldosterone synthase, among others. A complex picture of cross-talking, additive, or opposite regulatory mechanisms emerges that may help us understand some disease states of uncontrolled mineralocorticoid secretion.

Mechanism of angiotensin II-induced proliferation in bovine adrenocortical cells.

The peptide hormone angiotensin-II (AII) is a potent vasoconstrictor and major regulator of aldosterone synthesis. In addition, AII also has growth-promoting effects. We have recently shown that the lipoxygenase (LO) pathway of arachidonic acid plays a major role in AII-induced aldosterone synthesis in adrenal glomerulosa cells. The LO pathway is also involved in the vasopressor and renin-inhibitory effects of AII. However, the role of LO products in AII-induced mitogenic effects have not yet been investigated. In the present studies we have evaluated the role of the LO pathway in AII-induced proliferative responses in a bovine adrenocortical cell clone termed AC1 cells. In addition, the potential receptor type and mechanism of AII-induced proliferation was studied by evaluating the effect of specific nonpeptide type 1 and type 2 AII receptor antagonists and the role of protein kinase-C (PKC). AII-induced DNA synthesis was significantly attenuated by two structurally dissimilar LO inhibitors, baicalein and phenidone. In addition, the LO product 12-hydroxyeicosatetraenoic acid (12-HETE) itself caused a significant increase in DNA synthesis, suggesting that the 12-LO pathway in part plays a role in AII-mediated mitogenesis. AII-induced proliferative responses were blocked by the type 1 AII receptor antagonist. Both AII- and 12-HETE-induced increases in DNA synthesis were markedly inhibited by two PKC blockers, staurosporine and sangivamycin. Further, both AII and 12-HETE could activate PKC by translocating it from the cytosol to the membrane fraction, as determined by Western immunoblotting. These results suggest that both 12-LO activation and protein kinase-C have an important role in AII-induced adrenal cell proliferation.

Platelet-derived growth factor is a potent inhibitor of angiotensin II-induced aldosterone synthesis

Platelet-derived growth factor (PDGF) is a potent mitogen for several cell types. In addition, PDGF has vasoconstrictive action and shares some signal transduction mechanisms with angiotensin II (AII). In the present study, we have examined the effects of PDGF on basal and AII-induced aldosterone synthesis in freshly isolated rat adrenal glomerulosa cells. Recombinant human PDGF-BB caused a dose-dependent inhibition of AII-induced aldosterone synthesis being effective at concentrations as low as 10 −12 M. We also investigated possible mechanisms of action of PDGF. We have previously reported that the 12-lipoxygenase (LO) pathway of arachidonic acid plays a key role in AII-induced aldosterone synthesis. We thus examined whether PDGF action is mediated by changes in 12-LO activation. PDGF, at the same doses that blocked All-induced synthesis also significantly inhibited AII-induced increases in the 12-LO product, 12-hydroxyeicosatetraenoic acid (12-HETE) formation. Further, the addition of 12-HETE completely restored the stimulatory effect of AII during inhibition by PDGF. These results suggest that PDGF could act, at least in part, by inhibition of AII-induced 12-HETE formation. We also examined the role of diacylglycerol (DG) formation since we have previously reported that DG is the source of arachidonic acid for 12-HETE formation. We observed that both AII and PDGF stimulated [ 3H]arachidonic acid-labeled DG formation. However, PDGF did not alter AII-induced DG formation suggesting that PDGF action is not mediated by affecting AII-induced increases in DG. These results suggest that PDGF may play an important role in the regulation of aldosterone synthesis by acting as a potent negative modulator of AII action in the adrenal.

Changes in 5 alpha- and 5 beta-reductase pathways of aldosterone metabolism by dietary sodium.

The effects of dietary Na+ on 5 alpha- and 5 beta-reductase pathways of aldosterone metabolism in the liver were studied in male rats maintained on low, control, and high Na+ diets. A high Na+ diet caused significant increases in the synthesis of 5 beta-reduced metabolites, primarily 3 alpha, 5 beta-tetrahydroaldosterone; whereas a low Na+ diet stimulated the 5 alpha-reductase pathway causing increases in the synthesis of 5 alpha-dihydroaldosterone and 3 beta 5 alpha-tetrahydroaldosterone, as well as certain polar, hydroxylated metabolites of aldosterone. These studies demonstrate that dietary Na+, a known regulator of aldosterone synthesis, may also regulate enzymes involved in aldosterone metabolism in peripheral tissues.