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The molecular basis of glucocorticoid-remediable aldosteronism, a Mendelian cause of human hypertension
... Un rasgo distintivo del hiperaldosteronismo familiar tipo I es la presencia de una enzima quimérica, aldosterona sintasa, producida por el entrecruzamiento desigual de los genes que codifican las enzimas 11β-hidroxilasa (CYP11B1) y aldosterona sintasa (CYP11B2). Estos genes son 95% idénticos en la secuencia de nucleótidos [5][6][7][8] . La enzima 11β-hidroxilasa (gen CYP11B1) se expresa normalmente en ambas zonas de la corteza suprarrenal: fasciculada y glomerulosa, cataliza la biosíntesis de cortisol y aldosterona, respectivamente. ...
Background:
Familial hyperaldosteronism type I is caused by the generation of a chimeric aldosterone synthase enzyme (ASCE) which is regulated by ACTH instead of angiotensin II. We have reported that in vitro, the wild-type (ASWT) and chimeric aldosterone synthase (ASCE) enzymes are inhibited by progesterone and estradiol does not affect their activity.
Aim:
To explore the direct action of testosterone on ASWT and ASCE enzymes.
Material and methods:
HEK-293 cells were transiently transfected with vectors containing the full ASWT or ASCE cDNAs. The effect of testosterone on AS enzyme activities was evaluated incubating HEK-cells transfected with enzyme vectors and adding deoxycorticosterone (DOC) alone or DOC plus increasing doses of testosterone. Aldosterone production was measured by HPLC-MS/MS. Docking of testosterone within the active sites of both enzymes was performed by modelling in silico.
Results:
In this system, testosterone inhibited ASWT (90% inhibition at five pM, 50% inhibitory concentration (IC50) =1.690 pM) with higher efficacy andpotency than ASCE (80% inhibition at five pM, IC50=3.176 pM). Molecular modelling studies showed different orientation of testosterone in ASWT and ASCE crystal structures.
Conclusions:
The inhibitory effect of testosterone on ASWT or ASCE enzymes is a novel non-genomic testosterone action, suggesting that further clinical studies are needed to assess the role of testosterone in the screening and diagnosis of primary aldosteronism.
... FH is frequently caused by germline mutations of ion channels such as KCNJ5, CACNA1D, and CACNA1H and further classified into types I-IV according to its clinical and biochemical features [16,[26][27][28]. FH-I is also characterized by glucocorticoidremediable aldosteronism caused by crossover of both CY-Copyright © 2021 Korean Endocrine Society P11B2 and CYP11B1 genes, resulting in ectopic expression of CYP11B2 [29,30]. The etiology of FH-II, however, has remained unknown, although its possible association with germline CLCN2 mutations was previously proposed [31]. ...
Primary aldosteronism (PA) is the most common cause of secondary hypertension, and is associated with an increased incidence of cardiovascular events. PA itself is clinically classified into the following two types: unilateral PA, mostly composed of aldosterone-producing adenoma (APA); and bilateral hyperaldosteronism, consisting of multiple aldosterone-producing micronodules (APMs) and aldosterone-producing diffuse hyperplasia. Histopathologically, those disorders above are all composed of compact and clear cells. The cellular morphology in the above-mentioned aldosterone-producing disorders has been recently reported to be closely correlated with patterns of somatic mutations of ion channels including KCNJ5, CACNA1D, ATP1A1, ATP2B3, and others. In addition, in non-pathological adrenal glands, APMs are frequently detected regardless of the status of the renin-angiotensin-aldosterone system (RAAS). Aldosterone-producing nodules have been also proposed as non-neoplastic nodules that can be identified by hematoxylin and eosin staining. These non-neoplastic CYP11B2-positive nodules could represent possible precursors of APAs possibly due to the presence of somatic mutations. On the other hand, aging itself also plays a pivotal role in the development of aldosterone-producing lesions. For instance, the number of APMs was also reported to increase with aging. Therefore, recent studies indicated the novel classification of PA into normotensive PA (RAAS-independent APM) and clinically overt PA.
... A hallmark of familial hyperaldosteronism type I is the presence of a chimeric aldosterone synthase enzyme, which is formed by unequal crossing-over of the genes that encode 11β-hydroxylase (CYP11B1), and aldosterone synthase (CYP11B2) enzymes. These genes are 95% identical in nucleotide sequence [5][6][7][8]. The 11β-hydroxylase enzyme (CYP11B1 gene) is normally expressed in both: human adrenal fasciculate and glomerulose zones, catalyzes the biosynthesis of cortisol and aldosterone, respectively. ...
Background
Familial hyperaldosteronism type I is caused by the generation of a chimeric aldosterone synthase enzyme (ASCE) which is regulated by ACTH instead of angiotensin II. We have reported that in vitro, the wild-type (ASWT) and chimeric aldosterone synthase (ASCE) enzymes are inhibited by progesterone and estradiol did not affect.
Aim
To explore the direct action of testosterone on ASWT and ASCE enzymes.
Methods
HEK-293 cells were transiently transfected with vectors containing the full ASWT or ASCE cDNAs. The effect of testosterone on AS enzyme activities were evaluated incubating HEK-cells transfected with enzymes vectors and adding deoxycorticosterone (DOC) alone or DOC plus increasing doses of testosterone. Aldosterone production was measured by HPLC-MS/MS. Docking of testosterone within the active sites of both enzymes was performed.
Results
In this system, testosterone inhibited ASWT (90% inhibition at five µM, IC50=1.690 µM) with higher efficacy and potency than ASCE (80% inhibition at five µM, IC50=3.176 µM). Molecular modelling studies showed different orientation of testosterone in ASWT and ASCE crystal structures.
Conclusions
The inhibitory effect of testosterone on ASWT or ASCE enzymes is a novel non-genomic testosterone action, suggesting that further clinical studies are needed to assess the role of testosterone in the screening and diagnosis of primary aldosteronism.
... Molecular studies have characterized the genetic basis of GRA to be from the unequal crossing over between CYP11B1 (11 -hydroxylase) and CYP11B2 (aldosterone synthase) loci resulting in chimeric gene involving the 5 ACTH-responsive promoter of the 11 -hydroxylase gene to the 3 coding sequences of the aldosterone synthase [4,5]. This results in ectopic expression of aldosterone synthase in zona fasciculata under the modulation of ACTH resulting in ACTH mediated aldosteronism [4,6]. ...
Glucocorticoid remediable aldosteronism (GRA) is rare familial form of primary aldosteronism characterized by a normalization of hypertension with the administration of glucocorticoids. We present a case of GRA and thoracoabdominal aneurysm complicated by multiple aortic dissections requiring complex surgical and endovascular repairs. Registry studies have shown a high rate of intracranial aneurysms in GRA patients with high case fatality rates. The association of thoracoabdominal aneurysms with GRA has not been described, thus far, in literature. Studies have shown that high tissue aldosterone levels concomitant with salt intake have a significant role in the pathogenesis of aneurysms and this may explain the formation of aneurysms in the intracranial vasculature and aorta. The association of GRA with thoracic aortic aneurysms needs to be further studied to develop screening recommendations for early identification and optimal treatment. Also, the early use of mineralocorticoid antagonists may have a significant preventive and attenuating effect in aneurysm formation, an association which needs to be confirmed in future studies.
... Investigation into this overwhelming evidence for genetic factors to control the extent of our BP has led to some important gene discoveries for monogenic forms of hypertension, which are caused essentially by functional defects of single gene products. [20][21][22][23][24][25][26] Essential hypertension, which represents >90% of all forms of hypertension, is, however, a polygenic trait (ie, caused by many genes). Discovering the genetic basis of essential hypertension has remained a daunting task. ...
... [8] [9] [10] [11] [12] [13] [14] [15] ...
Discovering the genes that contribute to complex polygenic diseases represents a significant challenge. Investigating the structural genetic variations associated with these disorders may not be sufficiently informative about vulnerability genes modulated by the environment. Characterizing gene expression patterns does not identify the primary differences in gene structure. The convergence of global screening of gene expression patterns with extensive structural genomic information may be necessary to identify the gene clusters that contribute to these pervasive diseases. These integrative efforts, though promising, are in their early phases and will require further refinement.
... Parallel strategies have been adopted with similar success in other more complex multifactorial polygenic traits such as hypertension (Dominiczak et al., 2000). Genes such as 11-hydroxylase in glucocorticoid remediable aldosteronism have been shown to mediate the hereditary hypertension in these patients (Lifton et al., 1992 ). However, as in stroke genetics, narrowing heterogeneity and studying single gene and mendelian disorders has been found to limit the application to the broader patient population. ...
Sequencing of the human genome is nearing completion and biologists, molecular biologists, and bioinformatics specialists have teamed up to develop global genomic technologies to help decipher the complex nature of pathophysiologic gene function. This review will focus on differential gene expression in ischemic stroke. It will discuss inheritance in the broader stroke population, how experimental models of spontaneous stroke might be applied to humans to identify chromosomal loci of increased risk and ischemic sensitivity, and also how the gene expression induced by stroke is related to the poststroke processes of brain injury, repair, and recovery. In addition, we discuss and summarise the literature of experimental stroke genomics and compare several approaches of differential gene expression analyzes. These include a comparison of representational difference analysis we have provided using an experimental stroke model that is representative of stroke evolution observed most often in man, and a summary of available data on stroke differential gene expression. Issues regarding validation of potential genes as stroke targets, the verification of message translation to protein products, the relevance of the expression of neuroprotective and neurodestructive genes and their specific timings, and the emerging problems of handling novel genes that may be discovered during differential gene expression analyses will also be addressed.
Primary aldosteronism was first described almost 50 years ago by Conn [2].He predicted that aldosteronism was a common cause of hypertension. For many years internists did not consider primary aldosteronism to be common. It was thought that hypokalemia should be a prerequisite for investigating patients for primary aldosteronism.With this assumption about 0.5% of hypertensive patients had primary aldosteronism. In addition,sampling of blood with a tourniquet induces an increase in serum potassium, also contributing to the low number of patients with primary aldosteronism. However, over the last 10 years there have been an increasing number of reports from all over the world that primary aldosteronism may be much more common [4, 5, 15]. Many more patients could benefit by screening for primary aldosteronism, using the ratio plasma aldosterone/ plasma renin activity or plasma renin levels. It is difficult to standardize the aldosterone/renin ratio as different laboratory methods are used and since plasma renin activity will with increasing frequency be replaced by determination of plasma renin levels. Although it may be difficult to define the exact cut-off of the aldosterone/renin ratio, it is evident that such an increased ratio once confirmed is an excellent indication for further endocrinologic workup. Several studies have shown a prevalence of primary aldosteronism of between 5% and 13% in patients with hypertension and even higher in some patients with continued high blood pressure in spite of treatment with several antihypertensive medications (see review by Young [16]). Most of these patients are not hypokalemic.
The adrenal cortex synthesizes and releases steroid hormones, mainly mineralocorticoids and glucocorticoids. There is a functional zonation of the adrenal cortex and steroid synthesis is thoroughly regulated. Overproduction of aldosterone, primary aldosteronism, may be much more common than previously known and may be responsible for 10% of essential hypertension. Primary aldosteronism is characterized by autonomous production of aldosterone, suppressed renin activity, hypokalemia, and hypertension. The two most common forms are unilateral adenoma and bilateral hyperplasia. In spite of thorough clinical workup and careful histopathology it is often difficult to differentiate between adenoma and hyperplasia. The gene CYP11B2 encodes the steroid synthesizing enzymes for aldosterone production, while the genes CYP17 and CYP11B1 are needed for cortisol production. Most normal controls show expression of CYP11B2 in zona glomerulosa. Expression of CYP11B1 and CYP17 is seen in zona fasciculata and reticularis, whereas the expression of CYP21 is present in all three cortical layers. Adenomas from patients with primary aldosteronism show considerable variation in the expression of CYP11B2. Adenomas from patients with Cushing's syndrome have a strong expression of CYP11B1 and CYP17. In a patient material of 29 cases of primary aldosteronism, 4 patients had small nodules detected with expression of CYP11B2 gene. These nodules were not visualized on CT, whereas adrenal masses seen on CT in these patients showed CYP11B1 and CYP17 gene expression. This suggests that these small nodules are responsible for the aldosterone production and this is characteristic of nodular hyperplasia in patients with primary aldosteronism. In conclusion, this method to visualize mRNA gene expression of steroidogenic enzymes, and especially expression of CYP11B2, has increased the knowledge of adrenal pathophysiology. The results emphasize the value to include functional studies (venous sampling and/or scintigraphy) in the preoperative work up of patients with primary aldosteronism.
Hypertension is highly prevalent among people with diabetes, especially those with type 2 diabetes. While the genesis of hypertension in diabetes is multifactorial, it is clear that early dysfunction of the vasculature, related, in part, to abnormalities in modulation of vascular tone by nitric oxide, heralds development of hypertension in such individuals. Presence of hypertension substantially increases the risk of adverse outcomes with regard to both the CV and renal systems. Once nephropathy becomes manifest, i.e. elevation in serum creatinine and macroalbuminuria, lowering of blood pressure to the recommended guideline goals slows kidney disease progression and reduces CV risk to a greater extent than does glucose control. Based on recent guidelines if systolic blood pressure is >15–20 mmHg above the goal, two drugs should be started, one of which should to be a diuretic. Clearly, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers have also demonstrated benefits in these patients when used in concert with diuretics. The positive outcomes with diuretics relates clearly to their ability to lower blood pressure, especially in volume-expanded individuals, which is true of virtually all people with diabetes because of the effects of insulin on proximal tubular sodium reabsorption.
Keywords:
hypertension;
macroalbuminuria;
nephropathy;
ACE inhibitors;
endothelium;
microalbuminuria
Oral contraceptives and postmenopausal hormone therapy may induce hypertension through multiple mechanisms, including sodium and volume retention. Numerous studies have shown significant increases in blood pressure (BP) with the chronic administration of oral contraceptives as well as reversibility with discontinuation. The effects of different classes of oral contraceptive agents and hormonal replacement therapy on BP and associated effects on other cardiovascular risk factors are covered in this article. Novel hormonal replacement therapy that lowers BP is also discussed.
Glucocorticoids remain a valuable and necessary component of therapy for many diseases. Nonetheless, sustained glucocorticoid treatment increases potential for future cardiovascular disease through multiple pathways, resulting in a tradeoff between benefit and harm. This article explores the potential mechanisms of glucocorticoid-induced hyperglycemia and dyslipidemia. Interactions between glucocorticoids and other potential cardiovascular risk factors are also reviewed. Safe, alternate strategies for minimizing the need for glucocorticoids are urgently needed.
Salt-sensitive forms of hypertension have received considerable renewed attention in recent years. This article focuses on 2 main forms of salt-sensitive hypertension (familial or genetic primary aldosteronism [PA] and Gordon syndrome) and the current state of knowledge regarding their genetic bases. The glucocorticoid-remediable form of familial PA (familial hyperaldosteronism type I) is dealt with only briefly because it is covered in depth elsewhere.
Glucocorticoid-remediable aldosteronism (GRA) is a hereditary form of primary hyperaldosteronism and the most common monogenic cause of hypertension. A chimeric gene duplication leads to ectopic aldosterone synthase activity in the cortisol-producing zona fasciculata of the adrenal cortex, under the regulation of adrenocorticotropin (ACTH). Hypertension typically develops in childhood, and may be refractory to standard therapies. Hypokalemia is uncommon in the absence of treatment with diuretics. The discovery of the genetic basis of the disorder has permitted the development of accurate diagnostic testing. Glucocorticoid suppression of ACTH is the mainstay of treatment; alternative treatments include mineralocorticoid receptor antagonists.
Multiple hormonal factors play a major role in the functional and structural abnormalities of hypertension (HT). At present, the kidneys and, in particular, renal Na(+) retention are thought to constitute a primary and sustaining mechanism in the development of HT. However, the precise renal and hormonal mechanisms leading to increased Na(+) reabsorption and HT remain unknown. Because the vast majority of HT is primary, this article focuses on the major endocrine systems, the RAS, aldosterone, and the SNS, that play a prominent role in the pathogenesis of HT.
Primary aldosteronism is the most frequent cause of secondary hypertension. Three variants of familial hyperaldosteronism are known today. Early onset hypertension and severe target organ damage are hallmarks of the heritable forms. The underlying gene defect has already been identified in familial hyperaldosteronism type I. In type II and III research is ongoing. A highly variable phenotype often precludes the discovery of the familial appearance of these syndromes. Taking a sound family history is extremely important to discover the Mendelian pattern of inheritance. The identification of affected families is highly rewarding because all variants can potentially be cured or at least specifically treated. Testing the relatives of an index patient sometimes even allows preemptive treatment. However, the availability of specific treatment options necessitates a solid differentiation between the three syndromes to avoid unnecessary medical therapy or surgery.
Thesis (Ph. D.)--Texas Tech University, 1999. Includes bibliographical references.
To determine the independent and combined effects of three quantitative trait loci (QTL) for blood pressure in the Genetically Hypertensive (GH/Omr) rat by generating and characterizing single and combined congenic strains that have QTL on rat chromosomes (RNO) 2, 6, and 18 from the GH rat introduced into a hypertension resistant Brown Norway (BN) background.
Linkage analysis and QTL identification (genome wide QTL scan) were performed with MapMaker/EXP to build the genetic maps and MapMaker/QTL for linking the phenotypes to the genetic map. The congenic strains were derived using marker-assisted selection strategy from a single male F1 offspring of an intercross between the male GH/Omr and female BN/Elh, followed by 10 generations of selective backcrossing to the female BN progenitor strain. Single congenic strains generated were BN.GH-(D2Rat22-D2Mgh11)/Mcwi (BN.GH2); BN.GH-(D6Mit12-D6Rat15)/Mcwi (BN.GH6); and BN.GH-(D18Rat41-D18Mgh4)/Mcwi (BN.GH18). Blood pressure measurements were obtained either via a catheter placed in the femoral artery or by radiotelemetry. Responses to angiotensin II (ANGII), norepinephrine (NE), and baroreceptor sensitivity were measured in the single congenics.
Transferring one or more QTL from the hypertensive GH into normotensive BN strain was not sufficient to cause hypertension in any of the developed congenic strains. There were no differences between the parental and congenic strains in their response to NE. However, BN.GH18 rats revealed significantly lower baroreceptor sensitivity (beta=-1.25-/+0.17), whereas BN.GH2 (beta=0.66-/+0.09) and BN.GH18 (beta=0.71-/+0.07) had significantly decreased responses to ANGII from those observed in the BN (beta=0.88-/+0.08).
The failure to alter blood pressure levels by introducing the hypertensive QTL from the GH into the hypertension resistant BN background suggests that the QTL effects are genome background-dependent in the GH rat. BN.GH2 and BN.GH18 rats reveal significant differences in response to ANGII and impaired baroreflex sensitivity, suggesting that we may have captured a locus responsible for the genetic control of baroreceptor sensitivity, which would be considered an intermediate phenotype of blood pressure.
Hypertension is a complex trait of unknown cause in humans. Mice of the inbred strain BPH/2 serve as a rodent model of human hypertension and display elevated blood pressure compared with the hypotensive strain BPL/1. An F2 intercross of BPH/2 and BPL/1 and 2 backcrosses of BPL/1 with Mus spretus were used to perform interval linkage mapping for systolic blood pressure in a genome scan. Significant linkage was observed in the F2s on chromosome 10 (logarithm of the odds score [LOD]=4.9) and on chromosome 13 in the M spretus backcross (LOD=3.3), with additional suggestive LODs on chromosomes 2, 6, 8, and 18. In addition, several suggestive linkages were observed for phenotypes associated with human hypertension. Our study is the first reported genome-wide linkage scan for blood pressure genes in the mouse.
Formerly, fewer than 1% of patients with hypertension were believed to have primary hyperaldosteronism; however, recent studies have suggested a higher prevalence, in 5% to 10% of patients with hypertension. Hypokalemia is not necessary for the diagnosis and is probably a sign of more advanced disease. The best diagnostic test is the plasma aldosterone concentration to plasma renin activity (PAC/PRA) ratio. Excess aldosterone level has a deleterious effect on the cardiovascular system. Aldosteronomas should be differentiated from idiopathic hyperaldosteronism (IHA),because they are curable by laparoscopic adrenalectomy.
Primary aldosteronism (PA) is characterized by hypertension, hypokalemia and suppressed renin-angiotensin system caused by autonomous aldosterone production. The aim of this study was to localize mRNA expression of the genes coding for steroidogenic enzymes in adrenals from a group of patients with PA and relate this to clinical work-up, histopathology and outcome of adrenalectomy.
This was a retrospective study of 27 patients subjected to adrenalectomy for PA.
Clinical data were collected and follow-up of all patients was performed. Paraffin-embedded specimens were analyzed by the in situ hybridization technique, with oligonucleotide probes coding for the steroidogenic enzyme genes.
The resected adrenals had the histopathologic diagnosis of adenoma (11), adenoma and/or hyperplasia (15) or hyperplasia (1). CYP11B2 expression (indicating aldosterone production) was found in a dominant adrenal nodule from 22 patients. Fourteen of these had additional CYP11B2 expression in the zona glomerulosa. All 22 patients were cured of PA by adrenalectomy. One of these patients, who had additional high expression of CYP11B2 in the zona glomerulosa, was initially cured, but the condition had recurred at follow-up. Two patients had a mass shown on computed tomography without CYP11B2 but with CYP11B1 and CYP17 expression (indicating cortisol production). Instead their adrenals contained small nodules with CYP11B2 expression. These patients were not cured.
Clinical data, endocrinologic evaluation and histopathology in combination with mRNA in situ hybridization of steroidogenic enzyme genes provide improved opportunities for correct subclassification postoperatively of patients with primary aldosteronism. At present, the in situ hybridization method is of special value for analysis of cases not cured by adrenalectomy.
Hypertension is the most common risk factor for stroke, heart disease, and end-stage renal disease. Despite significant advances in the characterization of the physiological mechanisms that govern the regulation of blood pressure, the genetic and molecular bases of hypertension remain poorly understood. The completion of the draft sequence of the human genome, and recent advances in the identification and characterization of patterns of sequence variation in human populations, hold the promise that hypertension genomics will offer significant insights into disease pathophysiology and open new avenues for the development of novel therapeutic modalities. However, the emergence of the epigenotype as a major determinant of disease is likely to transform our genome-centric approaches toward more integrative and comprehensive strategies. This review provides an overview of the current progress of and future prospects for the application of genomic and epigenomic sciences to hypertension research.
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