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Best Practice & Research. Clinical... Mar 2001Abnormalities of mineralocorticoid synthesis and/or metabolism profoundly affect the regulation of electrolyte and water balance and of blood pressure. Characteristic... (Review)
Review
Abnormalities of mineralocorticoid synthesis and/or metabolism profoundly affect the regulation of electrolyte and water balance and of blood pressure. Characteristic changes in extracellular potassium, sodium and hydrogen ion concentrations are usually diagnostic. Serious deficiency may be acquired, for example in Addison's disease, or inherited. In most of the inherited syndromes, the precise molecular changes in specific steroidogenic enzymes have been identified. Mineralocorticoid excess may be caused by aldosterone or 11-deoxycorticosterone by inadequate conversion of cortisol to cortisone by 11beta-hydroxysteroid dehydrogenase type 2 in target tissues (see Chapter 4), by glucocorticoid receptor deficiency or by constitutive activation of renal sodium channels. Changes in electrolyte balance and renin as well as the abnormal pattern of corticosteroid metabolism are usually diagnostic. Where these abnormalities are inherited (e.g. 11beta- or l7alpha-hydroxylase deficiencies, glucocorticoid remediable hyperaldosteronism (GRA), receptor defects, Liddle's syndrome), the molecular basis is again usually known and, in some cases, may provide the simplest diagnostic tests. Primary aldosteronism, although readily identifiable, presents problems of differential diagnosis, important because optimal treatment is different for each variant. Moreover, the mechanisms by which the variants develop are poorly understood. Finally, a significant proportion of patients with essential hypertension show characteristics of mild mineralocorticoid excess, for example low renin levels. Is this relevant to pathophysiology and, if so, is the effect induced via classic mechanisms of action or through newly discovered direct actions on the brain, heart and blood vessels? These questions are the subject of current research.
Topics: Adrenal Cortex Hormones; Humans; Hypertension; Metabolic Diseases; Mineralocorticoids; Phenotype
PubMed: 11469810
DOI: 10.1053/beem.2000.0118 -
The Journal of Steroid Biochemistry and... Jan 1996"Mineralocorticoid receptors (MR) in the central nervous system" is something of a misnomer, in that the sites so designated almost certainly act predominantly as high... (Review)
Review
"Mineralocorticoid receptors (MR) in the central nervous system" is something of a misnomer, in that the sites so designated almost certainly act predominantly as high affinity receptors for glucocorticoid hormones in most areas of the brain, reflecting the equivalent affinity of MR for aldosterone, corticosterone and cortisol. In epithelial tissues, the enzyme 11 beta hydroxysteroid dehydrogenase-2 confers aldosterone-specificity on the otherwise non-selective MR, by converting physiologic glucocorticoids (but not aldosterone) to receptor-inactive 11-keto metabolites. Coding differences in guinea-pig ACTH and glucocorticoid receptors produce very high circulating free cortisol levels; guinea-pig MR have nonetheless similar high affinity for aldosterone and glucocorticoids as those in the rat, evidence for the lack of evolutionary drive towards lower affinity MR, and for an "always occupied" mode of action of CNS MR. Whether these "always occupied" MR act at composite response elements, by the formation of heterodimers with GR or other transcription factors, or by binding progesterone in the luteal phase, in pregnancy and in utero, remains to be established.
Topics: Animals; Brain Chemistry; Female; Gene Expression Regulation; Glucocorticoids; Guinea Pigs; Humans; Kidney; Mice; Mineralocorticoids; Nerve Tissue Proteins; Pregnancy; Protein Binding; Rats; Receptors, Glucocorticoid; Receptors, Mineralocorticoid; Sodium; Substrate Specificity; Tumor Cells, Cultured
PubMed: 8603039
DOI: 10.1016/0960-0760(95)00235-9 -
Molecular and Cellular Endocrinology Mar 2004For the past 50 years, the physiological action of aldosterone was considered to be on epithelial tissues to maintain fluid and electrolyte homeostasis. Recently, a... (Review)
Review
For the past 50 years, the physiological action of aldosterone was considered to be on epithelial tissues to maintain fluid and electrolyte homeostasis. Recently, a nonepithelial, pathophysiologic, proinflammatory role for aldosterone has been inferred from studies on mineralocorticoid/salt administration, with or without mineralocorticoid receptor (MR) blockade, in experimental animals, and from clinical studies such as RALES and EPHESUS. More recently still, it has become clear that the pathophysiologic trigger for the vascular inflammatory response observed is not necessarily aldosterone per se, but inappropriate activation of vascular wall MR. MR can be inappropriately activated by aldosterone in the context of an inappropriate salt status, or by glucocorticoids in the context of tissue damage. The studies supporting this latter conclusion, and the novel mechanisms proposed to support this concept, are details in the text to follow.
Topics: Aldosterone; Animals; Glucocorticoids; Humans; Mineralocorticoid Receptor Antagonists; Mineralocorticoids; Receptors, Mineralocorticoid; Vasculitis
PubMed: 15134827
DOI: 10.1016/j.mce.2003.10.054 -
Hormone and Metabolic Research =... Jun 2010Recent evidence indicates a greater frequency of primary aldosteronism (PA) among patients with hypertension than the previously accepted prevalence. PA was once... (Review)
Review
Recent evidence indicates a greater frequency of primary aldosteronism (PA) among patients with hypertension than the previously accepted prevalence. PA was once considered a relatively benign form of hypertension associated with low incidence of organ complications. Recent views, however, suggest that long-term exposure to increased aldosterone levels might result in cardiovascular, renal, and metabolic sequelae that occur independently of the blood pressure level. Cross-sectional comparisons with patients with essential hypertension have demonstrated that patients with PA are at higher risk of cardiovascular events, have more frequent left ventricular hypertrophy and diastolic dysfunction, have greater urinary albumin losses as a marker of a hemodynamic intrarenal adaptation, and are insulin resistant. Some of these findings have been corroborated by the results of short-term, follow-up studies where it was shown that unilateral adrenalectomy or treatment with mineralocorticoid receptor (MR) antagonists are effective in correcting hypertension and hypokalemia. Normalization of blood pressure and correction of hypokalemia, however, are not the only goals in managing PA and effective prevention of organ complications is mandatory in these patients. The relative efficacy of adrenalectomy and MR antagonists, in the long-term, on the cardiovascular, renal, and metabolic outcomes still needs evaluation, being the aldosterone-induced tissue damage the main factor that could justify the cost of increasing efforts in screening of disease and differentiation of subtypes. In this narrative review, we summarize the results obtained with either surgical or medical treatment of PA and outline the findings of long-term, prospective studies on the effects of treatment on cardiovascular and renal outcomes and on insulin sensitivity.
Topics: Adrenal Glands; Cardiovascular Diseases; Endocrine Surgical Procedures; Humans; Hyperaldosteronism; Kidney Diseases; Metabolic Diseases; Mineralocorticoid Receptor Antagonists; Mineralocorticoids
PubMed: 20119883
DOI: 10.1055/s-0029-1246185 -
Annual Review of Nutrition 1996Mineralocorticoids are adrenal steroid hormones that regulate the retention of sodium by the kidney and, hence, are crucial in the regulation of sodium balance,... (Review)
Review
Mineralocorticoids are adrenal steroid hormones that regulate the retention of sodium by the kidney and, hence, are crucial in the regulation of sodium balance, intravascular volume, and blood pressure. The molecular biology of mineralocorticoid biosynthesis and action has only recently been elucidated. The genes encoding the various enzymes that convert cholesterol to mineralocorticoids have now been cloned. This has revealed the molecular basis of several inherited forms of mineralocorticoid excess, which cause hypertension, and several forms of mineralocorticoid deficiency, which cause salt loss. The cloning of the mineralocorticoid receptor revealed a paradox. Both the mineralocorticoid and the glucocorticoid receptor are activated equally by cortisol, even though cortisol has very modest mineralocorticoid activity. This is explained by the cloning of two genes for the enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta HSD). Type-II 11 beta HSD, found primarily in the kidney, irreversibly converts cortisol to cortisone, which does not activate the mineralocorticoid receptor. Type-II 11 beta HSD thus defends the mineralocorticoid receptor from being activated by the very high concentrations of cortisol in the blood. Recent studies in genetically hypertensive rats suggest that other enzymes or factors that regulate salt balance may remain undiscovered. Thus the study of mineralocorticoid biosynthesis and action remains one of the most promising approaches to understanding hypertension.
Topics: Animals; Humans; Hypertension; Mineralocorticoids; Rats; Receptors, Mineralocorticoid; Wasting Syndrome
PubMed: 8839934
DOI: 10.1146/annurev.nu.16.070196.002303 -
Recent Progress in Hormone Research 1997This review, covering work from the Baker Institute and elsewhere, is divided into four sections. In the first a summary account of two areas-mineralocorticoid receptors... (Review)
Review
This review, covering work from the Baker Institute and elsewhere, is divided into four sections. In the first a summary account of two areas-mineralocorticoid receptors and the enzyme 11 beta hyderoxysteroid dehydrogenase-will be given as background. Next is a brief consideration of the three single-gene causes of human hypertension described to date-glucocorticoid-remediable aldosteronism. Liddle's syndrome, and apparent mineralocorticoid excess-in all of which abnormal sodium handling is a feature. Third, the sequelae of aldosterone occupancy of nonepithelial mineralocorticoid receptors will be analyzed in some detail by reviewing studies on experimental mineralocorticoid hypertension and cardiac fibrosis from this laboratory and elsewhere. Finally, three recent studies from this laboratory will be presented: on putative 11-ketosteroid receptors in epithelial tissue, on glucose-PKC potentiation of mineralocorticoid effects on heart cells, and on the necessity for factors/ processes other than the conversion of cortisol to cortisone (or, in the rat, corticosterone to 11-dehydrocorticosterone) to ensure aldosterone-specific effects in mineralocorticoid target tissues.
Topics: 11-beta-Hydroxysteroid Dehydrogenases; Humans; Hydroxysteroid Dehydrogenases; Hyperaldosteronism; Hypertension; Mineralocorticoids; Mutation; Receptors, Mineralocorticoid; Sodium; Syndrome
PubMed: 9238855
DOI: No ID Found -
Kidney International Apr 2000Aldosterone acts in mineralocorticoid-sensitive cells by binding to the mineralocorticoid receptor (MR). Because the MR displays similar affinity for aldosterone and... (Review)
Review
Aldosterone acts in mineralocorticoid-sensitive cells by binding to the mineralocorticoid receptor (MR). Because the MR displays similar affinity for aldosterone and glucocorticoid hormones and because these latter hormones are 100- to 1000-fold more abundant than aldosterone in the plasma, mechanisms are required to avoid permanent illicit occupancy of MR by glucocorticoid hormones. The main mechanism of mineralocorticoid selectivity is enzymatic: the 11beta hydroxysteroid dehydrogenase (HSD2) metabolizes glucocorticoid hormones into derivatives with a low affinity for MR. The cell biology and regulation of HSD2 are reviewed in this article, as well as its implications in human hypertension. Other factors play a role in mineralocorticoid selectivity: the MR itself, the possibility to form homodimers (MR-MR), or heterodimers (with the glucocorticoid receptor). All of these cellular events participate to successive dynamic equilibriums, which allow fine tuning of transcriptional regulation of target genes, depending on the target tissue and the hormonal status.
Topics: 11-beta-Hydroxysteroid Dehydrogenases; Aldosterone; Animals; Blood Pressure; Glucocorticoids; Humans; Hydroxysteroid Dehydrogenases; Hypertension; Mineralocorticoids
PubMed: 10760068
DOI: 10.1046/j.1523-1755.2000.00976.x -
Sheng Li Xue Bao : [Acta Physiologica... Dec 2022Mineralocorticoid receptor antagonists not only are used as a diuretics to treat essential hypertension, but also protect the heart and kidney by inhibiting inflammation... (Review)
Review
Mineralocorticoid receptor antagonists not only are used as a diuretics to treat essential hypertension, but also protect the heart and kidney by inhibiting inflammation and fibrosis. Since the discovery of spironolactone, the first generation of mineralocorticoid receptor antagonist, two types of non-steroid mineralocorticoid receptor antagonists (finerenone and esaxerenone) approved for clinical use have been developed, which have the advantages of high affinity, high selectivity and balanced distribution in heart and kidney, and can be used in clinic as a cardiorenal protective drug. In this paper, the development history of mineralocorticoid receptor antagonists was reviewed, and the pathophysiological mechanism of inflammation and fibrosis caused by mineralocorticoid receptors and the similarities and differences of different generations of mineralocorticoid receptor antagonists were analyzed. In particular, the phase III clinical research evidence of finerenone and esaxerenone was discussed. This paper also reviews the research progress of cardiorenal protection of non-steroid mineralocorticoid receptor antagonists in patients with chronic kidney disease.
Topics: Humans; Fibrosis; Heart Failure; Mineralocorticoid Receptor Antagonists; Mineralocorticoids; Renal Insufficiency, Chronic; Clinical Trials, Phase III as Topic
PubMed: 36594390
DOI: No ID Found -
Kidney International Apr 2000The mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR) share considerable structural and functional homology. Overlapping effects on epithelial sodium... (Comparative Study)
Comparative Study Review
The mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR) share considerable structural and functional homology. Overlapping effects on epithelial sodium transport are observed in vivo; in vitro, both are able to bind and transactivate through a common hormone response element. This has led several investigators to suggest that specificity is conferred primarily by prereceptor mechanisms, and we have addressed this question using both in vitro and in vivo approaches. Although the MR has been regarded as less transcriptionally active than the GR in vitro, significant differences are observed when epithelial rather than fibroblast cell lines are used. These differences are mediated by the N-termini of the receptors. Activation of intracellular signaling pathways differentially modulates MR- versus GR-mediated transactivation. Although these studies identify mechanisms by which specificity may be achieved, they do not prove that this occurs in vivo. Such studies have been limited by an absence of MR-regulated genes. Known candidate aldosterone-responsive genes have been examined in the rat distal colon; the time course and the specificity of the response to a single parenteral dose of corticosteroid has been characterized. The epithelial sodium channel beta and gamma subunit genes are both up-regulated within 60 minutes by either MR or GR activation. Similar responses are observed for the serum and glucocorticoid-regulated kinase and channel-inducing factor genes. All four genes show clear and rapid up-regulation of their mRNA levels by aldosterone, which is paralleled by GR-mediated up-regulation of expression. While they are indeed aldosterone-responsive genes, genes that are uniquely aldosterone-regulated remain to be identified.
Topics: Animals; Cells, Cultured; Gene Expression Regulation; Glucocorticoids; Humans; Mineralocorticoids; Substrate Specificity; Transfection
PubMed: 10760051
DOI: 10.1046/j.1523-1755.2000.00959.x -
Kidney International Dec 1992(1) Decreased 11 beta-OHSD activity permits binding of cortisol to the Type I (mineralocorticoid) receptor in humans, thereby producing spironolactone-inhibitable Na+...
(1) Decreased 11 beta-OHSD activity permits binding of cortisol to the Type I (mineralocorticoid) receptor in humans, thereby producing spironolactone-inhibitable Na+ retention, hypokalemia and hypertension, the syndrome of apparent mineralocorticoid excess (AME). (2) Blockade of either the Type I receptor with spironolactone or the Type II (glucocorticoid) receptor with RU-486 does not consistently abolish the effects of stress level cortisol on Na+ retention and hypertension in acute studies in normal humans, suggesting the existence of an additional glucocorticoid receptor. (3) Enhanced glucocorticoid 6 beta-hydroxylation could play an etiologic role in certain hypertensive syndromes. (4) Both decreased 11 beta-OHSD and increased 6 beta-OHase are candidates as intermediate phenotypes for the remote phenotype essential hypertension.
Topics: 11-beta-Hydroxysteroid Dehydrogenases; Animals; Glucocorticoids; Humans; Hydrocortisone; Hydroxysteroid Dehydrogenases; Hypertension; Mineralocorticoids; Receptors, Glucocorticoid
PubMed: 1474763
DOI: 10.1038/ki.1992.421