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Nephron. Physiology 2014Effects of mineralocorticoids are not restricted to regulation of epithelial salt transport, extracellular volume and blood pressure; mineralocorticoids also influence a... (Review)
Review
Effects of mineralocorticoids are not restricted to regulation of epithelial salt transport, extracellular volume and blood pressure; mineralocorticoids also influence a wide variety of seemingly unrelated functions such as inflammation and fibrosis. The present brief review addresses the role of mineralocorticoids in the orchestration of these latter processes. Mineralocorticoids foster inflammation as well as vascular, cardiac, renal and peritoneal fibrosis. Mechanisms involved in mineralocorticoid-sensitive inflammation and fibrosis include the serum- and glucocorticoid-inducible kinase 1 (SGK1), which is genomically upregulated by mineralocorticoids and transforming growth factor β (TGF-β), and stimulated by mineralocorticoid-sensitive phosphatidylinositide 3-kinase. SGK1 upregulates the inflammatory transcription factor nuclear factor-κB, which in turn stimulates the expression of diverse inflammatory mediators including connective tissue growth factor. Moreover, SGK1 inhibits the degradation of the TGF-β-dependent transcription factors Smad2/3. Mineralocorticoids foster the development of TH17 cells, which is compromised following SGK1 deletion. Excessive SGK1 expression is observed in a wide variety of fibrosing diseases including lung fibrosis, diabetic nephropathy, glomerulonephritis, obstructive kidney disease, experimental nephrotic syndrome, obstructive nephropathy, liver cirrhosis, fibrosing pancreatitis, peritoneal fibrosis, Crohn's disease and celiac disease. The untoward inflammatory and fibrosing effects of mineralocorticoids could be blunted or even reversed by mineralocorticoid receptor blockers, which may thus be considered in the treatment of inflammatory and/or fibrosing disease.
Topics: Animals; Fibrosis; Inflammation; Mice; Mineralocorticoids; Protein Serine-Threonine Kinases; Rats; Receptors, Mineralocorticoid; Th17 Cells; Transforming Growth Factor beta; Up-Regulation
PubMed: 25377230
DOI: 10.1159/000368267 -
The Journal of Clinical Endocrinology... Feb 2018Mineralocorticoid (MC) replacement therapy in patients with primary adrenal insufficiency (PAI) was introduced more than 60 years ago. Still, there are limited data on... (Review)
Review
CONTEXT
Mineralocorticoid (MC) replacement therapy in patients with primary adrenal insufficiency (PAI) was introduced more than 60 years ago. Still, there are limited data on how MC substitution should be optimized, because MC dosing regimens have only been systematically investigated in a few studies. We review the management of current standard MC replacement therapy in PAI and its plausible impact on outcome.
DESIGN
Using PubMed, we conducted a systematic review of the literature from 1939 to 2017, with the following keywords: adrenal insufficiency, MC deficiency, aldosterone, cardiovascular disease, hypertension, and heart failure.
RESULTS
The current standard treatment consists of fludrocortisone (FC) given once daily in the morning, aiming at normotension, normokalemia, and plasma renin activity in the upper normal range. Available data suggest that patients with PAI may be underreplaced with FC as symptoms and signs indicating chronic MC underreplacement, such as salt craving and postural dizziness persist, in many treated patients with PAI. Data acquired from large registry-based studies show that glucocorticoid doses for replacement in PAI are higher than those estimated from endogenous production. Glucocorticoid overreplacement may reduce the need of MC replacement but may also be a consequence of inadequate MC replacement.
CONCLUSIONS
The commonly used MC replacement in PAI may not be adequate in some patients. Insufficient MC substitution may be responsible for poor cardiometabolic outcome and the failure to restore well-being adequately in patients with PAI. Well-designed studies oriented at optimizing MC replacement therapy are urgently needed.
Topics: Adrenal Insufficiency; Hormone Replacement Therapy; Humans; Mineralocorticoids; Treatment Outcome
PubMed: 29156052
DOI: 10.1210/jc.2017-01928 -
Best Practice & Research. Clinical... Dec 2005Obesity is strongly associated with arterial hypertension. A positive correlation between obesity and plasma aldosterone levels has been observed by different... (Review)
Review
Obesity is strongly associated with arterial hypertension. A positive correlation between obesity and plasma aldosterone levels has been observed by different investigators, suggesting that an abnormal secretion of aldosterone in obesity contributes to the development of arterial hypertension in obese subjects. The mechanisms proposed to explain this abnormal aldosterone production mainly involve the adipose renin-angiotensin system, an indirect effect of increased fatty acids, and direct adrenal stimulation by adipocyte secretory products. Indeed, adipose mineralocorticoid-stimulating activity was recently observed in isolated human adipocytes, suggesting a hitherto unknown direct involvement of adipose tissue in the regulation of blood pressure in obesity.
Topics: Adipocytes; Adipose Tissue; Aldosterone; Blood Pressure; Humans; Hypertension; Mineralocorticoids; Obesity; Renin-Angiotensin System
PubMed: 16311217
DOI: 10.1016/j.beem.2005.07.002 -
Current Hypertension Reports Jun 2015The impaired capacity of the kidney to excrete sodium plays an essential role in the development of hypertension. Adrenal corticosteroids control renal handling of... (Review)
Review
The impaired capacity of the kidney to excrete sodium plays an essential role in the development of hypertension. Adrenal corticosteroids control renal handling of sodium by regulating tubular sodium reabsorption in the distal nephron where both mineralocorticoid receptors (MR) and glucocorticoid receptors are expressed. In addition, cell type- and segment-specific expression of 11β-HSD2 and sodium transporters such as Na-Cl cotransporter (NCC), epithelial sodium channel (ENaC), and pendrin/Na(+)-driven Cl(-)/HCO3 (-) exchanger (NDCBE) builds a distinctive model of sodium transport in the aldosterone-sensitive distal nephron. Aberrant MR activation in the distal nephron triggers salt-sensitive hypertension and hypokalemia through inappropriate sodium reabsorption and potassium secretion. However, MR activity is not necessarily modulated by the ligand alone. Recently, several lines of evidence revealed alternative mechanisms that regulate the activity of MR in a ligand-independent manner or through ligand binding modulation. This review summarizes the disorders related to MR activation in individual tubular cells and highlights the renal mechanism of salt-sensitive hypertension and new approaches for the prevention and treatment of this disease.
Topics: Animals; Humans; Hypertension; Kidney; Mineralocorticoids; Receptors, Mineralocorticoid; Sodium Chloride, Dietary
PubMed: 25903070
DOI: 10.1007/s11906-015-0552-2 -
Journal of Endocrinological... 1995Apparent mineralocorticoid excess (AME) is a syndrome attributable to congenital deficiency of the enzyme 11 beta-dehydrogenase (11 beta-OHSD) which converts active... (Review)
Review
Apparent mineralocorticoid excess (AME) is a syndrome attributable to congenital deficiency of the enzyme 11 beta-dehydrogenase (11 beta-OHSD) which converts active glucocorticoid cortisol to inactive cortisone. When 11 beta-OHSD activity is impaired, cortisol acts as a potent mineralocorticoid and causes hypertension and hypokalemia with a suppression of the renin-angiotensin-aldosterone system. The increased ratio of urinary cortisol/cortisone metabolites and a prolonged half-life of cortisol are useful for the diagnosis. Dexamethasone and/or potassium sparing diuretics have been used for medication of AME. Licorice ingestion induces a mineralocorticoid excess state, and it seems that this is the result of acquired inhibition of 11 beta-DH by glycyrrhetinic acid. The existence of a second 11 beta-OHSD isoform has been suggested strongly for a long time, and recently, a human 11 beta-OHSD 2 cDNA has been isolated. It appears that 11 beta-OHSD 2 conveys specificity upon the renal MR, and a defect in its activity seems likely to account for the phenotype of AME.
Topics: 11-beta-Hydroxysteroid Dehydrogenases; Animals; Humans; Hydrocortisone; Hydroxysteroid Dehydrogenases; Hypertension; Hypokalemia; Mineralocorticoids; Syndrome
PubMed: 9221270
DOI: 10.1007/BF03349763 -
The Journal of Steroid Biochemistry and... Apr 1993We studied in vitro and in vivo corticosteroid production as well as the presence of symptoms of an increased mineralocorticoid effect in patients with 'silent' adrenal... (Review)
Review
We studied in vitro and in vivo corticosteroid production as well as the presence of symptoms of an increased mineralocorticoid effect in patients with 'silent' adrenal cortical adenomas, and compared these results to those found in patients with classical mineralocorticoid excess syndromes. We found that under in vitro conditions, cells from 'silent' adrenal cortical adenomas (n = 19) produced substantial amounts of both zona glomerulosa and fasciculata steroids, although the production of steroids in these cells was lower compared to that in mineralocorticoid-producing adenoma cells (n = 26). Patients with aldosterone-producing and 'silent' adenomas had significantly increased plasma atrial natriuretic peptide levels, which remained non-suppressible after upright posture and furosemide administration. Of the 25 patients with 'silent' adenomas, 11 had low and non-stimulable plasma renin activity (PRA) before but, in most cases, not after adrenal surgery. When compared to those with normal PRA (n = 14), patients with low PRA 'silent' adenomas (n = 11) had higher blood pressure which was significantly reduced after surgery, and a mild hypokalemia before but not after surgery. Although basal plasma concentrations of aldosterone, 18-hydroxy-corticosterone, corticosterone, deoxycorticosterone, 18-hydroxy-DOC, cortisol,11-deoxycortisol and 17-hydroxy-progesterone (17-OH-P) were not increased in either groups of 'silent' adenomas, ACTH stimulation produced a hyperreactive response for all measured steroids, of which an extremely high 17-OH-P seemed to be one of the most intriguing findings. We consider that these observations in 'silent' adrenal cortical adenomas may justify surgical intervention, irrespective of the size and potential malignancy of these adenomas.
Topics: Adenoma; Adrenal Cortex Neoplasms; Humans; Mineralocorticoids; Syndrome
PubMed: 8481352
DOI: 10.1016/0960-0760(93)90122-d -
Heart Failure Reviews Jan 2005Mineralocorticoid receptors (MR) bind both mineralocorticoids and glucocorticoids with high affinity (deoxycorticosterone = corticosterone >/= aldosterone = cortisol),... (Review)
Review
Mineralocorticoid receptors (MR) bind both mineralocorticoids and glucocorticoids with high affinity (deoxycorticosterone = corticosterone >/= aldosterone = cortisol), and are found in both Na(+) transporting epithelia (e.g. kidney, colon) and nonepithelial tissues (e.g. heart, brain). MR evolved before aldosterone synthase, consistent with their acting in nonepithelial tissues as high affinity glucocorticoid receptors, essentially always occupied by normal levels of endogenous glucocorticoids. In epithelial tissues the enzyme 11beta hydroxysteroid dehydrogenase Type 2 (11betaHSD2) allows aldosterone to selectively activate MR, by converting cortisol to cortisone and NAD to NADH. 11betaHSD2 debulks intracellular cortisol by 90%, to levels approximately 10-fold those of aldosterone, so that when the enzyme is operating most epithelial MR are occupied but not activated by cortisol. When intracellular redox state is changed-by inhibition of 11beta HSD2, generation of reactive oxygen species, or intracellular introduction of oxidised glutathione (GSSG)-cortisol changes from an MR antagonist to an MR agonist. This bivalent activity of cortisol appears to underlie the therapeutic efficacy of MR blockade in heart failure (RALES, EPHESUS) and in essential hypertension, providing a rationale for MR blockade in cardiovascular disease not characterized by elevated aldosterone levels. Its wider (patho)physiologic implications, particularly for neurobiology, remain to be explored.
Topics: 11-beta-Hydroxysteroid Dehydrogenases; Aldosterone; Glucocorticoids; Humans; Hydrocortisone; Mineralocorticoids; Reactive Oxygen Species; Receptors, Mineralocorticoid
PubMed: 15947887
DOI: 10.1007/s10741-005-2344-2 -
Journal of Human Hypertension Feb 2021Recent studies have expanded our understanding of the actions of the mineralocorticoid receptor (MR) to a diverse array of tissue types that differ substantially from... (Review)
Review
Recent studies have expanded our understanding of the actions of the mineralocorticoid receptor (MR) to a diverse array of tissue types that differ substantially from the epithelial cells of the renal nephron. In these cell types the role of the MR has been largely, but not exclusively, defined in terms of pathogenic signalling pathways leading to tissue injury and remodelling. Macrophages and cardiomyocytes are two cell types in which the MR plays a central role in the cardiac tissue response to injury, renovascular hypertension and oxidative stress for example. Macrophages are critical for resolution of tissue injury and wound healing and their pleiotropic actions are central to the development of many forms of heart, renal and vascular disease. The MR in cardiomyocytes is not only essential for the chronotropic and ionotropic actions of mineralocorticoids in the short and longer term, but also for induction of hypertrophic and proinflammatory signalling programs. The present review discusses recent studies, presented at the Aldosterone and Hypertension Satellite of the 15th Asian-Pacific Congress of Hypertension, investigating new mechanisms for MR signalling in these cells and how their dysfunction contributes to the onset and progression of cardiovascular disease and heart failure.
Topics: Aldosterone; Cardiovascular Diseases; Humans; Mineralocorticoid Receptor Antagonists; Mineralocorticoids; Receptors, Mineralocorticoid
PubMed: 32733061
DOI: 10.1038/s41371-020-0386-5 -
Steroids Jan 1995An association between mineralocorticoids and hypertension has been recognized for over 50 years, although the mechanisms involved are not entirely clear. In addition to... (Review)
Review
An association between mineralocorticoids and hypertension has been recognized for over 50 years, although the mechanisms involved are not entirely clear. In addition to the hypertension seen in cases of frank mineralocorticoid excess, such as in an aldosterone-producing adenoma, many essential hypertensive patients respond to treatments mitigating mineralocorticoid action, even though circulating levels of these steroids are within normal ranges. It has been a decade since David Bohr hypothesized that a center within the brain, probably in the AV3V area, was responsible for the orchestration of the multiple homeostatic mechanisms controlling blood pressure. It was proposed that the "set point" for such a center was dependent upon intracellular Ca + + and/or another ion content or transport across cell membranes, and was altered by mineralocorticoids and in some forms of genetic hypertension. The focus of this paper is the role of the central nervous system in mineralocorticoid hypertension. The importance of these data resides in the possibility that the central mechanisms involved in mineralocorticoid hypertension may also be operant in the pathogenesis of other forms of hypertension, as well as in the normal control of blood pressure.
Topics: Animals; Blood Pressure; Brain; Cerebral Ventricles; Homeostasis; Hypertension; Infusions, Parenteral; Mineralocorticoids
PubMed: 7792819
DOI: 10.1016/0039-128x(94)00004-v -
Journal of Endocrinological... 1995
Review
Topics: Animals; Glucocorticoids; Humans; Hyperaldosteronism; Mineralocorticoids; Pseudohypoaldosteronism; Rats; Receptors, Glucocorticoid; Receptors, Mineralocorticoid
PubMed: 9221274
DOI: 10.1007/BF03349767