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Mineralocorticoid receptors (MRs) are transcriptional regulators that mediate the diverse physiological and pathophysiological actions of corticosteroid hormones across many tissues. In the kidney aldosterone control of sodium/water resorption via DNA-binding actions of the MR is established. MRs also regulate tissues not involved in electrolyte homeostasis such as the heart, adipose tissue, brain, and inflammatory cells where the MRs can respond to both aldosterone and cortisol. The pathology of inappropriate MR activation in non-epithelial tissues are well-described, and steroidal antagonists of the MR have been clinically beneficial in the management of heart failure and blood pressure for decades. However, the role of cortisol-dependent MR activation in the physiological setting is less well defined. Like other steroid hormone receptors, the MR also regulates non-DNA-binding pathways including MAPK pathways and G protein coupled receptors to provide diversity to MR signaling. Whether nonDNA binding pathways are more relevant for MR activation in non-epithelial, versus epithelial, tissues remain unclear. This review will focus on molecular regulation of ligand-dependent MR activation and the physiology and pathophysiology of MR actions in the heart with a focus on the cardiomyocyte and provide a discussion of relevant genomic and non-genomic MR pathways and potential new transcriptional partners for the MR and their relevance for health and disease. Understanding MR actions in the heart will provide new insights into cell-selective mechanisms that underpin the therapeutic benefits of MRAs, and are a critical step towards developing next-generation tissue selective MR modulators with improved safety profiles.

Background. Earlier we found that even in intact rats, certain parameters of nitrogenous metabolism fluctuate in a fairly wide range, which further expands in cases of prolonged water loads. Based on this, we have been created three groups that are homogeneous in the parameters of nitrogenous metabolism. We have been shown that each cluster is accompanied by a specific constellation of immune parameters. In this study, an attempt will be made to supplement the immune accompaniment of each constellation of nitrogenous metabolites with parameters of the autonomic nervous and endocrine systems. Material and methods. Experiment was performed on 60 healthy female Wistar rats, both intact and loaded with different mineral waters. Immune status was assessed by thymocytogram, splenocytogram, blood leukocytogram and immunocytogram, as well as by phagocytosis parameters of blood neutrophils and monocytes. The state of autonomous regulation assessed by HRV. The plasma levels of the hormones of adaptation: corticosterone, triiodothyronine and testosterone (by the ELISA) were determined as well as mineralocorticoid, calcitonin and parathyroid activity calculated by their electrolyte markers. Results. 9 neuro-endocrine and 17 immune parameters were identified, the set of which three clusters of nitrogen metabolism clearly differ from each other. The overall accuracy of the classification is 93,3%. Conclusion. The variety of states of exchange of nitrogenous metabolites is accompanied by specific constellations of 26 parameters of neuro-endocrine-immune complex.

Pendrin is a Cl−/HCO3− exchanger selectively present in the intercalated cells of the kidney. Although experimental studies have demonstrated that pendrin regulates blood pressure downstream of the renin-angiotensin-aldosterone system, its role in human hypertension remains unclear. Here, we analyzed the quantitative changes in pendrin in urinary extracellular vesicles (uEVs) isolated from a total of 30 patients with primary aldosteronism (PA) and from a rat model of aldosterone excess. Western blot analysis revealed that pendrin is present in dimeric and monomeric forms in uEVs in humans and rats. In a rodent model that received continuous infusion of aldosterone with or without concomitant administration of the selective mineralocorticoid receptor (MR) antagonist esaxerenone, pendrin levels in uEVs, as well as those of epithelial Na+ channel (ENaC) and Na-Cl-cotransporter (NCC), were highly correlated with renal abundance. In patients with PA, pendrin levels in uEVs were reduced by 49% from baseline by adrenalectomy or pharmacological MR blockade. Correlation analysis revealed that the magnitude of pendrin reduction after treatment significantly correlated with the baseline aldosterone-renin ratio (ARR). Finally, a cross-sectional analysis of patients with PA confirmed a significant correlation between the ARR and pendrin levels in uEVs. These data are consistent with experimental studies showing the role of pendrin in aldosterone excess and suggest that pendrin abundance is attenuated by therapeutic interventions in human PA. Our study also indicates that pendrin analysis in uEVs, along with other proteins, can be useful to understand the pathophysiology of hypertensive disorders.

Background and purpose Mineralocorticoid receptors (MRs), glucocorticoid receptors (GRs) and corticotropin-releasing factor (CRF) in the paraventricular nucleus of hypothalamus (PVN) are involved in the response to stress. The present study investigated the role of GRs and MRs in the PVN in regulating depressive and anxiety-like behaviours. Experimental approach To model chronic stress, rats were exposed to corticosterone treatment via drinking water for 21 days, and GR antagonist RU486 and MR antagonist spironolactone, alone and combined, were directly injected in the PVN daily for the last 7 days of corticosterone treatment. Behavioural tests were run on days 22 and 23. Depressive- and anxiety-like behaviours were evaluated in forced swim test, sucrose preference test, novelty-suppressed feeding test and social interaction test. The expression of GRs, MRs and CRF were detected by western blot. Key results Rats exposed to corticosterone exhibited depressive- and anxiety-like behaviours. The expression of GRs and MRs decreased, and CRF levels increased in the PVN. The intra-PVN administration of RU486 increased the levels of GRs and CRF without influencing depressive- or anxiety-like behaviours. The spironolactone-treated group exhibited an increase in MRs without influencing GRs and CRF in the PVN and improved anxiety-like behaviours. Interestingly, the intra-PVN administration of RU486 and spironolactone combined restored expression of GRs, MRs and CRF and improved depressive- and anxiety-like behaviours. Conclusion and implications In this rat model of stress, the simultaneous restoration of GRs, MRs and CRF in the PVN might play an important role in the treatment of depression and anxiety.

The Epithelial Na+ Channel, ENaC, comprised of 3 subunits (αβγ, or sometimes δβγENaC), plays a critical role in regulating salt and fluid homeostasis in the body. It regulates fluid reabsorption into the blood stream from the kidney to control blood volume and pressure, fluid absorption in the lung to control alveolar fluid clearance at birth and maintenance of normal airway surface liquid throughout life, and fluid absorption in the distal colon and other epithelial tissues. Moreover, recent studies have also revealed a role for sodium movement via ENaC in nonepithelial cells/tissues, such as endothelial cells in blood vessels and neurons. Over the past 25 years, major advances have been made in our understanding of ENaC structure, function, regulation, and role in human disease. These include the recently solved three-dimensional structure of ENaC, ENaC function in various tissues, and mutations in ENaC that cause a hereditary form of hypertension (Liddle syndrome), salt-wasting hypotension (PHA1), or polymorphism in ENaC that contributes to other diseases (such as cystic fibrosis). Moreover, great strides have been made in deciphering the regulation of ENaC by hormones (e.g., the mineralocorticoid aldosterone, glucocorticoids, vasopressin), ions (e.g., Na+ ), proteins (e.g., the ubiquitin-protein ligase NEDD4-2, the kinases SGK1, AKT, AMPK, WNKs & mTORC2, and proteases), and posttranslational modifications [e.g., (de)ubiquitylation, glycosylation, phosphorylation, acetylation, palmitoylation]. Characterization of ENaC structure, function, regulation, and role in human disease, including using animal models, are described in this article, with a special emphasis on recent advances in the field. © 2021 American Physiological Society. Compr Physiol 11:1-29, 2021.

Obesity impairs endothelial-mediated vasodilation, the earliest step in vascular disease and a contributor to hypertension. We previously demonstrated that endothelial cell mineralocorticoid receptor (MR) deletion prevents obesity-induced microvascular dysfunction in females by increasing nitric oxide-mediated vasodilation. Estrogen receptor alpha (ERα) can oppose MR function, therefore we hypothesized that ERα mediates the benefits of endothelial MR deficiency. Females lacking endothelial MR or wildtype littermates were fed control or high fat diet for 20 weeks to cause obesity. MR deletion improved mesenteric artery endothelial-dependent vasodilation in obese females and ERα inhibition ex vivo negated this protective effect. Endothelial MR deletion results in significantly more ERα mRNA and protein. In vitro, estrogen increases endothelial nitric oxide synthase phosphorylation, which is inhibited by aldosterone and dependent on MR. Both proteins co-immunoprecipitate with striatin and a mimetic peptide that disrupts ERα-striatin binding also decreased MR-striatin interaction. Finally, removing endothelial MR in obese females restored endothelial function by increasing the nitric oxide component of vasodilation. Combined deletion of endothelial ERα negated the benefit of endothelial MR deletion. These results indicate that endothelial ERα prevents the detrimental effects of MR in obesity by increasing nitric oxide to rescue vasodilation in females. MR and ERα may compete for striatin binding within endothelial cells to regulate nitric oxide. These data identify a novel mechanism that promotes MR antagonism to prevent obesity-induced microvascular dysfunction in females.

The ability of gestobutanoyl, a pregnane steroid with progestogenic activity, to exhibit additional glucocorticoid, mineralocorticoid, antiandrogenic, and estrogenic effects in rats has been studied. It was found that gestobutanoyl did not have estrogenic activity because it did not increase the weight of the uterus with prolonged (30 d) administration at a therapeutic dose of 0.25 mg/kg and doses 10 and 100 times higher. Gestobutanoyl at a dose of 2.5 mg/kg for 30 d did not show glucocorticoid activity because the thymus mass did not change. However, the thymus mass decreased by 25% (p ≤ 0.05) when gestobutanoyl was administered at a dose 100 times higher (25 mg/kg) than the therapeutic dose. Gestobutanoyl at a dose of 2.5 mg/kg reduced the expression of androgen receptor (AR) mRNA in the rat uterus by 3 times and, as previously shown, did not increase the weight of the prostate and levator ani muscle. The mineralocorticoid activity of gestobutanoyl tablets was studied using peroral administration for 14 d to female rats at doses 100 and 1000 times (2.5 and 25 mg/kg, respectively) the therapeutic dose. Diuresis did not decrease, water was not retained in the rat body, and electrolytes were excreted in the urine and were present in the urine at constant concentrations in all experimental groups, indicating the absence of side mineralocorticoid effects of gestobutanoyl tablets.

The mineralocorticoid receptor (MR) and its ligand aldosterone have been found to play a major role in the pathophysiology of depression. Both could be targets of therapeutic interventions. We analyzed laboratory data and questionnaires evaluating anxiety (using GAD-7 questionnaire) and depression (using PHQD questionnaire) of up to 210 patients with primary aldosteronism (PA) (82 females, 54.7 ± 12.0yrs; 128 males, 48.7 ± 12.8yrs) before and one year after initiation of specific treatment of PA by either adrenalectomy (ADX) or treatment with mineralocorticoid receptor antagonists (MRA). After ADX normalization of aldosterone excess was observed. This was associated with a significant reduction of depressive symptoms, but no significant change in GAD-7 score. MRA treatment was accompanied with persistent high aldosterone levels, but led to a significant improvement of anxiety, but no significant changes in PHQD scores. These data suggest different mechanistic pathways for depression and anxiety mediated via the MR. For treatment of depression a reduction of aldosterone levels might be relevant at CNS locations specific for aldosterone, whereas MRA targets MR more broadly, including areas, where cortisol is the main ligand. MRA may be useful in treatment of anxiety related behavior.

Serum and glucocorticoid-regulated kinase 1 (SGK1) stimulates aldosterone-dependent renal Na reabsorption and modulates blood pressure. In addition, genetic ablation or pharmacological inhibition of SGK1 limits the development of kidney inflammation and fibrosis in response to excess mineralocorticoid signaling. In this work, we tested the hypothesis that a systemic increase in SGK1 activity would potentiate mineralocorticoid/salt-induced hypertension and kidney injury. To that end, we used a transgenic mouse model with increased SGK1 activity. Mineralocorticoid/salt-induced hypertension and kidney damage was induced by unilateral nephrectomy and treatment with deoxycorticosterone acetate and NaCl in the drinking water for 6 wk. Our results show that although SGK1 activation did not induce significantly higher blood pressure, it produced a mild increase in glomerular filtration rate, increased albuminuria, and exacerbated glomerular hypertrophy and fibrosis. Transcriptomic analysis showed that extracellular matrix-and immune response-related terms were enriched in the downregulated and upregulated genes, respectively, in transgenic mice. In conclusion, we propose that systemically increased SGK1 activity is a risk factor for the development of mineralocorticoid-dependent kidney injury in the context of low renal mass and independently of blood pressure. NEW and NOTEWORTHY Increased activity of the protein kinase serum and glucocorticoid-regulated kinase 1 may be a risk factor for accelerated renal damage. Serum and glucocorticoid-regulated kinase 1 expression could be a marker for the rapid progression toward chronic kidney disease and a potential therapeutic target to slow down the process. © 2021 American Physiological Society. All rights reserved.

Background. We have previously shown that nitrogenous metabolites have immunomodulatory effects, both suppressor and enhancing, both in healthy rats and in humans exposed to pathogenic influences. The immunomodulatory effect of bilirubin is probably mediated through aryl hydrocarbon receptors, and uric acid through TL- and adenosine receptors of immune cells. The question of mediators of the immunomodulatory action of urea and creatinine remains open. We hypothesized the mediating role of mediators of the autonomic nervous system and adaptive hormones. The aim of this study is to analyze the relationships between the parameters of nitrogenous metabolites and the parameters of the autonomic nervous and endocrine systems, on the one hand, and between neuroendocrine and immune parameters - on the other hand. Material and methods. Experiment was performed on 60 healthy female Wistar rats. The plasma levels and urinary excretion of the nitrogenous metabolites, HRV and endocrine (corticosterone, triiodothyronine and testosterone plasma levels, calcitonin, parathyroid and mineralocorticoid activities, the thickness of glomerular, fascicular, reticular and medullar zones of adrenals) parameters as well as parameters of immunity were determined. Results. According to the results of canonical correlation analysis, the modulating effects of nitrogenous metabolites on neuroendocrine parameters are quite pronounced and almost identical in terms of bilirubin (R=0,603), creatinine (R=0,602), uric acid (R=0,599) and urea (R=0,586). Taken together, nitrogenous metabolites determine neuroendocrine parameters by 71,5% (R=0,845; χ2(84)=179; p-6). Triiodothyronine, fascicular and medullar areas of the adrenal glands, vagal tone and calcitonin activity were the most susceptible to nitrogenous metabolites. In turn, neuroendocrine parameters determine the parameters of immunity, subject to exposure to nitrogenous metabolites, by 95,8% (R=0,979; χ2(264)=405; p-6). Conclusion. Previously identified immunomodulatory effects of nitrogenous metabolites are realized, perhaps, through the factors of the autonomic nervous and endocrine systems.

Aim. To assess the influence of the pathogenetic action of the succinate-containing drug on corticosteroid regulation in the kidney of rats with different resistance to hypoxia during recovery after systemic circulation arrest. Methods. The object of the study was male non-inbred white rats weighing 200220 g. A week after testing for resistance to hypoxia, a 5-minute systemic circulation arrest was simulated by intrathoracic clamping of the vascular bundle of the heart, followed by resuscitation. In the postresuscitation period, the experimental rats were once daily injected with a solution containing inosine + nicotinamide + riboflavin + succinic acid, and the control rats 0.9% Sodium Chloride solution. The observation period was 35 days. We studied the content of corticosterone, aldosterone in blood plasma, gluco- and mineralocorticoid receptors, carbonylated proteins, dityrosine, and products that react with thiobarbituric acid in homogenates of the kidneys. Statistical data were presented as mean and standard deviation M. Nonparametric KruskalWallis (N) and MannWhitney (U) tests followed by Dunn test, Spearman correlation analysis were used. Differences were considered statistically significant at p 0.05. Results. The use of succinate-containing preparation reduced the intensity of free radical processes in both groups of animals. Against this background, in low-resistance rats, on the 1st day, the concentration of glucocorticoid receptors statistically significantly increased to 117% (p 0.05), and then was comparable to the control; the greatest statistically significant changes in the level of mineralocorticoid receptors occurred on the 1st day (increase by 25%, p 0.001) and at 2135th days (decrease by 2230%, p 0.001). In highly resistant rats, the correction led to a shift in the maximum content of glucocorticoid receptors from the last day (134% of the control level, p 0.01 without therapy) to the 1st (123%, p 0.05 with succinate-containing therapy) and maintaining the receptors level comparable to the initial, in the future. The level of mineralocorticoid receptors in highly resistant rats was lower than in low resistant rats, both in the group without correction and with correction. Conclusion. Correction of the course of the postresuscitation period with a succinate-containing drug in animals with a low resistance to hypoxia against the background of a decrease in the intensity of carbonyl stress and restoration of feedback mechanisms causes stabilization of glucocorticoid receptors level and a decrease in mineralocorticoid receptors to control values by the end of the experiment; in organisms highly resistant to hypoxia, against the background of correction, the activity of lipid peroxidation decreases and the level of both types of receptors are restored.

The kidney plays a critical role in human health and deviation from its normal function can lead to severe morbidity and mortality. Exposure to excess testosterone in women has been linked to several disorders, including kidney disorder and acting undoubtedly through androgen receptor (AR), whereas the involvement of mineralocorticoid receptor (MR) is unclear. Likewise, the renal effect of sodium acetate (SAc) during late gestational exposure to testosterone is not well known. We hypothesized that SAc or MR blockade would protect the kidney of testosterone-exposed pregnant rats against glutathione and adenosine depletion. Twenty-five pregnant Wistar rats were treated (sc) with olive oil, testosterone propionate (0.5 mg/kg) singly or in combination with SAc (200 mg/kg; p.o.), androgen receptor (AR) blocker, flutamide (Flu; 7.5 mg/kg; p.o.) or (MR) blocker, eplerenone (Eple; 0.5 mg/kg) between gestational days 14 and 19. Glutathione, adenosine and nitric oxide were decreased while uric acid (UA), xanthine oxidase (XO), malondialdehyde (MDA), lactate dehydrogenase activity and free fatty acids were increased in the kidneys of gestational rats exposed to testosterone. Also, plasma urea and creatinine were elevated. SAc and Eple reversed tested testosterone-induced effects in gestational rats. The exposure to testosterone impairs renal antioxidant defense via AR and MR during late gestation in pregnant rats. The study also provides evidence that sodium acetate protects the kidneys of gestational testosterone-exposed rats against defective antioxidant defense in like manner as MR or AR antagonist.

As are other artificial glucocorticoids, dexamethasone is widely used in everyday obstetric practice. The threat of termination of pregnancy is an indication for the use of glucocorticoids. However, there is evidence that the introduction of glucocorticoids during pregnancy can lead to impaired brain development and behavior of offspring that can be caused by a change in the activity of the hypothalamic–pituitary–adrenocortical system (HPAS) due to past effects. The aim of the present work was to study the effect of the introduction of synthetic hormone dexamethasone at the 14th–16th (DM14–16) and 17th–19th (DM17–19) days of prenatal ontogenesis on the stress reactivity of the HPAS in adult 3-month-old rats, as well as on the level of gluco- (GR) and mineralocorticoid (MR) receptors in the most vulnerable areas of the brain (hippocampus and neocortex). Significant intergroup differences in the dynamics of a change in the level of corticosterone in the blood of adult rats in response to a weak stress effect (rapid stress reactivity test) were detected. Using the immunohistochemical method, changes in the expression (the amount of immunopositive cells) of GR and MR were studied in CA1 field and dentate gyrus (DG) of the hippocampus, as well as in second and fifth neocortex layers in adult male rats. In animals of the DM14–16 group, a significant decrease in the number of cells intensively stained using antibodies to GR in CA1 field, hippocampus DG, and neocortex layer V (to 24.5, 32.4, and 5.5%, respectively) as compared with the control were observed. The introduction of dexamethasone at the 17th–19th day of gestation also led to a decrease in the amount of intensively stained GR-immunopositive cells in the hippocampus CA1 field and neocortex layer V (to 31.9 and 35.7%, respectively), but to a lesser degree than in animals from the group DM14–16. A trend toward a decrease in the number of GR-positive cells is accompanied by an increase in immunoreactivity of the cells to MR. Thus, the introduction of dexamethasone at different periods of prenatal ontogenesis modifies the work of gluco- and mineralocorticoid receptors; however, the degree, localization, and direction of these changes differ depending on the time of the effect.

Background Altered function of the hypothalamic–pituitary–adrenal (HPA) axis in type 2 diabetic patients, a condition preceded by pre-diabetes, has been shown to increase the risk of depression as well as cause downstream effects resulting in upregulation of gluconeogenesis and dyslipidemia. In addition, stress, either psychological from managing diabetes or lifestyle related, further activates the HPA axis causing an exaggerated stress response. This study investigated the activity of the HPA axis in selected markers of glucose handling, and the stress response relative to components of the HPA axis in a diet-induced pre-diabetic rat model. Methods Sprague Dawley Rats were randomly divided into non-pre-diabetic group (NPD) and pre-diabetic group (PD) (n = 6, per group) over a 20-week induction period and a further 12-week experimental period to get 32 weeks. At the end of the 20 and 32-week periods, glucose handling using the Homeostasis Model Assessment indices, adrenocorticotropic (ACTH) and corticosterone (CORT) concentrations were measured. Stress was induced and the forced swim test were performed in the 12-week experimental week. At the end of 32 weeks glucocorticoid and mineralocorticoid hippocampal receptors were also measured. Results Impaired glucose handling in the PD group as well as increase in corticosterone was observed at the end of both 20 and 32-week periods by comparison to NPD groups. No changes were observed in ACTH concentration at week 20 while, at week 32, a decrease in plasma ACTH concentration was observed in the PD group by comparison to the NPD group. The stressed-induced animals were stressed using the forced swim test: the behaviour observed showed an increase in immobility time in the PD stressed group by comparison to the NPD group. This was followed by the observation of a decrease in ACTH and CORT concentration in the PD stressed group by comparison to the NPD stressed group. Mineralocorticoid and glucocorticoid receptors gene expression were elevated in the stressed PD group relative to the stressed NPD group. Conclusion These observations, together, suggest that diet-induced pre-diabetes is associated with impaired HPA axis activity and deteriorating response to stress.

In primary aldosteronism (PA), the occurrence of K+ loss and hypertension suggest alterations in renal tubular transport, but the molecular basis of these alterations in humans is unclear. In this study, urinary extracellular vesicles (uEVs) isolated from patients undergoing fludrocortisone suppression testing (FST, as a means of confirming or excluding PA) were analyzed using mass spectrometry-based proteomics to determine the combined effects of an aldosterone analogue, NaCl and KCl supplementation on renal tubular protein abundance. Of quantified proteins, the Cl−/HCO3− exchanger pendrin decreased by a median 37% [−15, 57] (P < 0.01) and the potassium channel ROMK increased by a median 31% [−10, 85] (P < 0.01) during FST among 10 PA subjects. The trends remained, but to a lesser degree, in two subjects cured of PA by unilateral adrenalectomy. In PA subjects, plasma K+ increased from median 3.6 to 4.2 mM (P < 0.01) and 24 h urine K+ from 101 to 202 mmol (P < 0.01), while 24 h urine Na+/K+ decreased from 2.3 to 0.8 (P < 0.01). At baseline, pendrin negatively correlated with plasma K+ (P < 0.05) and positively correlated with plasma aldosterone (P < 0.01). There were no clear correlations between Δ pendrin (Δ = D4–D0) and changes in blood or urine variables, and no correlations between ROMK in any of the blood or urine variables either at baseline or during FST. We conclude that oral co-administration of mineralocorticoid and KCl in PA patients is associated with reduced pendrin and enhanced ROMK in uEVs. Pendrin reduction during FST suggests that the suppressive effects of oral KCl may outweigh pendrin upregulation by mineralocorticoids.

This review covers the last 80 years of remarkable progress in the development of mineralocorticoid receptor (MR) antagonists (MRAs) from synthesis of the first mineralocorticoid to trials of nonsteroidal MRAs. The MR is a nuclear receptor expressed in many tissues/cell types including the kidney, heart, immune cells, and fibroblasts. The MR directly affects target gene expression—primarily fluid, electrolyte and haemodynamic homeostasis, and also, but less appreciated, tissue remodelling. Pathophysiological overactivation of the MR leads to inflammation and fibrosis in cardiorenal disease. We discuss the mechanisms of action of nonsteroidal MRAs and how they differ from steroidal MRAs. Nonsteroidal MRAs have demonstrated important differences in their distribution, binding mode to the MR and subsequent gene expression. For example, the novel nonsteroidal MRA finerenone has a balanced distribution between the heart and kidney compared with spironolactone, which is preferentially concentrated in the kidneys. Compared with eplerenone, equinatriuretic doses of finerenone show more potent anti-inflammatory and anti-fibrotic effects on the kidney in rodent models. Overall, nonsteroidal MRAs appear to demonstrate a better benefit–risk ratio than steroidal MRAs, where risk is measured as the propensity for hyperkalaemia. Among patients with Type 2 diabetes, several Phase II studies of finerenone show promising results, supporting benefits on the heart and kidneys. Furthermore, finerenone significantly reduced the combined primary endpoint (chronic kidney disease progression, kidney failure, or kidney death) vs. placebo when added to the standard of care in a large Phase III trial.

espanolEl hiperaldosteronismo y el hipoaldosteronismo responden a una secrecion excesiva o insuficiente de aldosterona, respectivamente, por las glandulas suprarrenales. Las causas mas frecuentes de hiperaldosteronismo primario incluyen la hiperplasia bilateral idiopatica y el adenoma productor de aldosterona. El hipoaldosteronismo hiporreninemico es la causa mas frecuente de hipoaldosteronismo aislado. El hiperaldosteronismo primario se caracteriza por hipertension arterial, hipopotasemia y alcalosis metabolica y el hipoaldosteronismo por hiperpotasemia y acidosis metabolica. El cribado del hiperaldosteronismo primario consiste en la medicion del cociente aldosterona/actividad de renina plasmatica (ARP). Si resulta elevado, se recomiendan pruebas funcionales (sobrecarga salina intravenosa u oral, supresion con fludrocortisona o captopril). Una vez confirmado el diagnostico, se debe realizar un estudio de imagen mediante tomografia computarizada (TC) abdominal y, en pacientes candidatos a cirugia, cateterismo de venas adrenales. En el hipoaldosteronismo se debe demostrar la incapacidad de secrecion de renina y aldosterona tras pruebas funcionales estimuladoras (cambios posturales y deplecion de volumen). En el hiperaldosteronismo primario por hiperplasia o adenoma unilateral, se recomienda adrenalectomia laparoscopica unilateral; cuando la afectacion es bilateral y en pacientes desestimados para cirugia, se realizara tratamiento con antagonistas del receptor mineralocorticoide-espironolactona como primera eleccion. En el hipoaldosteronismo, restriccion de potasio y terapia mineralocorticoide sustitutiva con fludrocortisona. EnglishHyper- and hypoaldosteronism are caused by an excessive or insufficient adrenal secretion of aldosterone, respectively. Idiopathic bilateral hyperplasia and aldosterone-producing adenoma are the commonest causes of primary hyperaldosteronism. Primary hyperaldosteronism is characterized by hypertension, hypokalemia and metabolic alkalosis; in turn, hypoaldosteronism presents hyperkalemia and metabolic acidosis. The aldosterone/plasma renin activity ratio (ARR) is routinely used as a screening test of primary hyperaldosteronism. Functional tests are recommended if ARR is high (salt-loading, intravenous or oral, and fludrocortisone or captopril suppression). Once diagnostic is confirmed, imaging studies (abdominal computed tomography —CT—) and adrenal vein catheterization (in patients for surgery) have to be performed. Plasma levels of aldosterone and renin activity have to be determined by stimulatory functional tests (response to posture and volume depletion tests). Unilateral laparoscopic adrenalectomy is recommended in primary hyperaldosteronism caused by unilateral hyperplasia or adenoma; mineralocorticoid (spironolactone) receptor antagonists are the first-choice treatment for bilateral cases and in patients considered unfit for surgery. Potassium restriction and mineralocorticoid replacement therapy with fludrocortisone is the treatment of hypoaldosteronism.

Purpose: To compare the macular morphology of good and poor responders to eplerenone treatment in chronic central serous chorioretinopathy (CSCR) patients. Methods: 30 eyes of 29 patients with chronic CSCR were treated with 50 mg/day oral eplerenone and followed up for one year. The integrity of outer retinal layers at baseline was assessed using optical coherence tomography. Patients who showed complete resolution of subretinal fluid at one year were assigned to the good responder group (Group 1), whilst those who showed moderate or no resolution were classified as poor responders (Group 2). Results: Ellipsoid zone interruption, ELM interruption and hyperreflective foci in outer segment (OS) and outer nuclear layer (ONL) was significantly more frequent in Group 2 than in Group 1 (pConclusion: There is higher chance of the resolution of subretinal fluid after eplerenone treatment in CSCR patients with intact outer retinal layers at baseline. Baseline morphologic evaluation of the outer retinal layers on OCT scans can be useful in predicting the response to mineralocorticoid receptor antagonist therapy in these patients.

Previously, we showed that global knockout (KO) of the circadian clock transcription factor PER1 in male, but not female, mice fed a high-salt diet plus mineralocorticoid treatment (HS/DOCP) resulted in nondipping hypertension and decreased night/day ratio of sodium (Na) excretion. Additionally, we have shown that the endothelin-1 (ET-1) gene is targeted by both PER1 and aldosterone. We hypothesized that ET-1 would exhibit a sex-specific response to HS/DOCP treatment in PER1 KO. Here we show that male, but not female, global PER1 KO mice exhibit a decreased night/day ratio of urinary ET-1. Gene expression analysis revealed significant genotype differences in ET-1 and endothelin A receptor (ETA) expression in male, but not female, mice in response to HS/DOCP. Additionally, both wild-type and global PER1 KO male mice significantly increase endothelin B receptor (ETB) expression in response to HS/DOCP, but female mice do not. Finally, siRNA-mediated knockdown of PER1 in mouse cortical collecting duct cells (mpkCCDc14) resulted in increased ET-1 mRNA expression and peptide secretion in response to aldosterone treatment. These data suggest that PER1 is a negative regulator of ET-1 expression in response to HS/DOCP, revealing a novel mechanism for the regulation of renal Na handling in response to HS/DOCP treatment.

The recent demonstration of the significant reduction in mortality in patients with septic shock treated with adjunctive glucocorticoids combined with fludrocortisone and the effectiveness of angiotensin II in treating vasodilatory shock have renewed interest in the role of the mineralocorticoid axis in critical illness. Glucocorticoids have variable interactions at the mineralocorticoid receptor. Similarly, mineralocorticoid receptor–aldosterone interactions differ from mineralocorticoid receptor–glucocorticoid interactions and predicate receptor–ligand interactions that differ with respect to cellular effects. Hyperreninemic hypoaldosteronism or selective hypoaldosteronism, an impaired adrenal response to increasing renin levels, occurs in a subgroup of hemodynamically unstable critically ill patients. The suggestion is that there is a defect at the level of the adrenal zona glomerulosa associated with a high mortality rate that may represent an adaptive response aimed at increasing cortisol levels. Furthermore, cross-talk exists between angiotensin II and aldosterone, which needs to be considered when employing therapeutic strategies.

Objective: It is to evaluate the functional state of the adrenal cortex after surgical treatment in patients with corticosteromas for optimize of tactic of postoperative management.Materials and methods: We examined 143 patients (43 men and 100 women) aged 51.3 ± 10.1 years with incidentaloma of adrenal glands and 27 healthy peopels (control group) aged 45.5 ± 5.7 years. Cushing's syndrome was detected in 22 patients, autonomous cortisol secretion was detected in 43. All patients had an analysis of the complaints, objective, laboratory and instrumental data in the preoperative and early postoperative periods. Assessment of levels glucocorticoid and mineralocorticoid hormones in biological fluids was carried out by immunoassay and high performance liquid chromatography.Results: The signs of adrenal cortex insufficiency in the early postoperative period were obtained in 77.3% of patients with Cushing's syndrome and in 25% of patients with autonomous cortisol secretion according to immunoassay and high performance liquid chromatography. An increase of level of corticosterone in the serum of blood in the preoperative period indicate the possibility development of adrenal insufficiency in the early postoperative period in all patients. Аn increase of levels of 11-deoxycortisol and 18-OH-corticosteronein in the serum of blood аnd urinary excretion of free cortisone, 18-OH-corticosterone and 6β-hydroxycortisol indicate the possibility development of adrenal insufficiency in the early postoperative period in patients with Cushing's syndrome.Conclusions: The determination of cortisol and aldosterone precursors by high performance liquid chromatography increases the accuracy of the diagnosis of glucocorticoid and mineralocorticoid function of the adrenal cortex in patients with Cushing's syndrome and with autonomous cortisol secretion in the early postoperative period.

Background Recent emerging evidence suggests that extra-adrenal synthesis of aldosterone occurs (e.g., within the failing heart and in certain brain areas). In this study, the authors investigated evidence for a local endogenous aldosterone production through its key processing enzyme aldosterone synthase within peripheral nociceptive neurons. Methods In male Wistar rats (n = 5 to 8 per group) with Freund’s complete adjuvant hind paw inflammation, the authors examined aldosterone, aldosterone synthase, and mineralocorticoid receptor expression in peripheral sensory neurons using quantitative reverse transcriptase–polymerase chain reaction, Western blot, immunohistochemistry, and immunoprecipitation. Moreover, the authors explored the nociceptive behavioral changes after selective mineralocorticoid receptor antagonist, canrenoate-K, or specific aldosterone synthase inhibitor application. Results In rats with Freund’s complete adjuvant–induced hind paw inflammation subcutaneous and intrathecal application of mineralocorticoid receptor antagonist, canrenoate-K, rapidly and dose-dependently attenuated nociceptive behavior (94 and 48% reduction in mean paw pressure thresholds, respectively), suggesting a tonic activation of neuronal mineralocorticoid receptors by an endogenous ligand. Indeed, aldosterone immunoreactivity was abundant in peptidergic nociceptive neurons of dorsal root ganglia and colocalized predominantly with its processing enzyme aldosterone synthase and mineralocorticoid receptors. Moreover, aldosterone and its synthesizing enzyme were significantly upregulated in peripheral sensory neurons under inflammatory conditions. The membrane mineralocorticoid receptor consistently coimmunoprecipitated with endogenous aldosterone, confirming a functional link between mineralocorticoid receptors and its endogenous ligand. Importantly, inhibition of endogenous aldosterone production in peripheral sensory neurons by a specific aldosterone synthase inhibitor attenuated nociceptive behavior after hind paw inflammation (a 32% reduction in paw pressure thresholds; inflammation, 47 ± 2 [mean ± SD] vs. inflammation + aldosterone synthase inhibitor, 62 ± 2). Conclusions Local production of aldosterone by its processing enzyme aldosterone synthase within peripheral sensory neurons contributes to ongoing mechanical hypersensitivity during local inflammation via intrinsic activation of neuronal mineralocorticoid receptors. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

In women and females of different species of laboratory animals, oestrogens stimulate the renin–angiotensin–aldosterone system (RAAS) by increasing tissue and circulating levels of angiotensinogen and renin during the preovulatory period. Progesterone and cortisol compete with aldosterone for mineralocorticoid receptors, which results in increased Na+ reabsorption during the postovulatory period. The purpose of the current research was to analyse the relationship of oestradiol-17β, progesterone and cortisol with RAAS in 23 mares during an oestrous cycle. During the preovulatory period, significant positive correlations of oestradiol-17β with renin and aldosterone concentrations and negative correlations of progesterone with renin and aldosterone concentrations were found. In contrast, during the postovulatory period, oestradiol-17β concentrations were positively correlated with angiotensin concentrations and progesterone was negatively correlated with this component of the RAAS. Cortisol concentrations were not correlated with the hormones of the RAAS, neither before nor after ovulation. This research demonstrates that, as occurs in other species, changes in the RAAS during the periovulatory period in mares may be modulated by variations in the concentrations of steroid hormones.

Introduction. Mineralocorticoids mainly affect the exchange of electrolytes, promote retention in the body of sodium, chlorides and water, and accelerate the excretion of potassium, calcium and magnesium. Their synthesis and blood supply are regulated mainly by angiotensin-II, which makes it possible to consider aldosterone as a part of renin-angiotensin-aldosteon system, which ensures the proper state of water-salt metabolism and hemodynamics. The purpose. Consider the relationship of dynamic balance of mineralocorticoids in patients with kidney and adrenal lesions. Material and methods. Review of contemporary and foreign literary sources; techniques - description, analysis, abstracting. Results. The pathogenesis of the development and progression of adrenal and kidney damage is closely associated with impaired synthesis, absorption of mineralocorticoids. The glucocorticoid activity of aldosterone roughly corresponds to 1/3 of cortisone. Main target organs of the hormone are salivary glands and kidneys. In the kidneys, aldosterone enhances sodium reabsorption. In pathological cases, the prolonged presence of chlorides and water in the body leads to the development of edema, hypernatremia, hypokalemia, hypervolemia, arterial hypertension, and sometimes, to the development of congestive heart failure. It poses particular danger in patients with impaired renal function. Deoxycorticosterone acetate (DOCSA) is a synthetic analogue of the Mineralocorticoids of the adrenal cortex. The drug is indicated for rapid-flowing adrenal hypofunction (addisonism), for myasthenia (increases muscle tone and performance), shock and trauma, for hypocorticism. Spironolactone is effective in swelling associated with increased aldosterone production, congestive heart failure, liver cirrhosis and nephrotic syndrome. Conclusions. Patients with kidney and adrenal lesions may have a violation of mineralocorticoid homeostasis, for the correction of which synthetic mineralocorticoids and their analogues, mineral and glucocorticoid antagonists, are used.

Aim. To characterize the peculiarities of the dynamics of the level of corticosteroid receptors in the myocardium of animals with different resistance to hypoxia in the post-resuscitation period. Methods. Experimental studies were carried out on male non-inbred white rats, divided into 2 groups by hypoxia resistance. A 5-minute arrest of the systemic circulation was modeled under ether anesthesia with intrathoracic clamping of the cardiovascular cluster with subsequent resuscitation. The observation period was 35 days. The content of corticosterone and aldosterone was determined in the blood plasma, the concentration of glucocorticoid and mineralocorticoid receptors in myocard homogenates was determined as well. Results. On days 1 to 3 of the post-resuscitation period in rats highly resistant to hypoxia, the dynamics of plasma corticosterone concentration and the content of corticosteroid receptors was unidirectional. Starting from the 5th day, against the background of a statistically significant decrease in the level of plasma corticosterone, a gradual increase in the density of corticosteroid receptors, mostly glucocorticoid, was observed, most pronounced on the 14th day and remaining until the end of the observation. In animals with low resistance to hypoxia, the dynamics of corticosteroid receptors was characterized by a predominance of mineralocorticoid content in almost all periods of observation. On days 13 of post-resuscitation period on the background of high concentrations of corticosteroid hormones, the minimum content of glucocorticoid receptors was noted. A decrease in the mineralocorticoid receptor level was recorded only on the first day, and in all subsequent periods of the experiment, the control indicators were significantly higher by 1.41.6 times. Strengthened mineralocorticoid signaling in the myocardium, characteristic of animals with low resistance to hypoxia, may be associated with the development of hypertrophy and fibrosis, inflammation, impaired electrical function. An increase in glucocorticoid receptors, characteristic of animals with a high resistance to hypoxia, has an adaptive effect, limiting the inflammatory response, the potential mechanism may be associated with increased expression of type 11-hydroxysteroid dehydrogenase. Conclusion. The identified features can have a significant influence on the course of the post-resuscitation period and determine the long-term forecast.

Unlike sex steroids, mineralocorticoids have attracted limited attention in ovarian physiology. Recent studies on primates have indicated possible local synthesis and action of mineralocorticoids in the ovary. Here, we examined developmental changes in the levels of mineralocorticoids and expression of genes encoding their biosynthetic enzymes and receptor in the bovine ovary. The follicles and corpora lutea (CL) were collected from F1 heifers. Expression levels of 21α-hydroxylase (CYP21A2), 11β-hydroxylase-1 (CYP11B1), and the mineralocorticoid receptor (NR3C2) in granulosa cells (GC), thecal layers (TL), and CL tissues were quantified by real-time PCR, whereas mineralocorticoids in the follicular fluid were measured by enzyme immunoassay (EIA). TL and GC expressed CYP21A2 and NR3C2, whereas CYP11B1 was expressed at very low or undetectable levels. The expression levels of these genes were not significantly different among small/large and healthy/atretic follicles but were higher in TL than in GC. CYP21A2 and NR3C2 were expressed in all CL stages with higher expression observed in the mid-stage. CYP11B1 expression was only apparent in the mid-stage CL. Aldosterone was detected in all follicles, and its concentration was not significantly different among the follicular groups. In paired large-healthy/atretic follicles, the concentration of deoxycorticosterone, a precursor of aldosterone, was approximately ten-fold higher than that of aldosterone and not significantly different between healthy and atretic follicles. In conclusion, the presence of mineralocorticoids and expression of NR3C2 in the bovine follicle together with the developmental change in the expression of CYP21A2, CYP11B1, and NR3C2 in the CL suggest possible endocrine/paracrine/autocrine roles of mineralocorticoids in the bovine ovary.

Contains fulltext : 244176.pdf (Publisher’s version ) (Closed access) Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders affecting cortisol biosynthesis. Reduced activity of an enzyme required for cortisol production leads to chronic overstimulation of the adrenal cortex and accumulation of precursors proximal to the blocked enzymatic step. The most common form of CAH is caused by steroid 21- hydroxylase deficiency due to mutations in CYP21A2. Since the last publication summarizing CAH in Endocrine Reviews in 2000 there have been numerous new developments. These include more detailed understanding of steroidogenic pathways, refinements in neonatal screening, improved diagnostic measurements utilizing chromatography and mass spectrometry coupled with steroid profiling, and improved genotyping methods. Clinical trials of alternative medications and modes of delivery have been recently completed or are under way. Genetic and cell-based treatments are being explored. A large body of data concerning long-term outcomes in patients affected by CAH, including psychosexual well-being, has been enhanced by the establishment of disease registries. This review provides the reader with current insights in congenital adrenal hyperplasia with special attention to these new developments.

Objectives To investigate kidney function by determining serum symmetric dimethylarginine (sSDMA) and serum creatinine (sCr) concentrations in dogs with primary hypoadrenocorticism (PH) receiving long-term mineralocorticoid replacement therapy. Methods Dogs with PH receiving a minimum of 12 months of either desoxycorticosterone pivalate or fludrocortisone acetate were included in the study provided that banked frozen serum samples were available for sSDMA analysis. sCr concentrations were retrieved from the medical records. In dogs still alive and presented for regular re-evaluations and in newly diagnosed patients, blood was prospectively collected for sSDMA and sCr determination. Results Thirty-two dogs met the inclusion criteria. The treatment time ranged from 12 to 146 months after initial diagnosis (median, 55.5 months). The majority of dogs had normal sSDMA and sCr concentrations throughout the hormone replacement treatment. Both sSDMA and sCr concentrations were persistently elevated in three of 32 dogs. Further workup confirmed chronic kidney disease (CKD) in all three dogs. Conclusions Based on these data, the prevalence of CKD could be higher in dogs with PH receiving long-term mineralocorticoid replacement treatment than in the general dog population. However, additional studies with a larger number of dogs are needed to confirm it.

Sodium appetite is an innate behavior occurring in response to sodium depletion that induces homeostatic responses such as the secretion of the mineralocorticoid hormone aldosterone from the zona glomerulosa of the adrenal cortex and the stimulation of the peptide hormone angiotensin II (ANG II). The synergistic action of these hormones signals to the brain the sodium appetite that represents the increased palatability for salt intake. This narrative review summarizes the main data dealing with the role of mineralocorticoid and ANG II receptors in the central control of sodium appetite. Appropriate keywords and MeSH terms were identified and searched in PubMed. References to original articles and reviews were examined, selected, and discussed. Several brain areas control sodium appetite, including the nucleus of the solitary tract, which contains aldosterone-sensitive HSD2 neurons, and the organum vasculosum lamina terminalis (OVLT) that contains ANG II-sensitive neurons. Furthermore, sodium appetite is under the control of signaling proteins such as mitogen-activated protein kinase (MAPK) and inositol 1,4,5-thriphosphate (IP3). ANG II stimulates salt intake via MAPK, while combined ANG II and aldosterone action induce sodium intake via the IP3 signaling pathway. Finally, aldosterone and ANG II stimulate OVLT neurons and suppress oxytocin secretion inhibiting the neuronal activity of the paraventricular nucleus, thus disinhibiting the OVLT activity to aldosterone and ANG II stimulation.

An extensive database of sterols and triterpenoids isolated from Ganoderma mushrooms was evaluated by in silico structure-based virtual screening to determine their respective ligand affinities for the glucocorticoid or mineralocorticoid receptor (GCR or MNR). The main ligands for GCR in our database were ergosta-7,22-dien-3-one (compound 1) and ganodermaside B (compound 2), while the best ligands for MNR were 2β,3α,9α-trihydroxyergosta-7,22-diene (compound 8) and 5α-ergosta-7,22-dien-3β-ol (compound 3). The binding free energy (BFE) values calculated for such metabolites were similar to those of the natural ligands for each receptor (i.e., dexamethasone for GCR and aldosterone for MNR). Moreover, the differences between mean BFE values calculated for both receptors suggest that ergosta-7,22-dien-3-one (compound 1), ganodermaside B (compound 2), fungisterol (compound 5), ganoderic acid Ma (compound 9), and cerevisterol (compound 10) might be used as specific ligands for GCR, with a significantly lower affinity for MNR. Finally, it is worth noting that even though this work is exclusively theoretical, the reported bioactivities (either pro- or anti-inflammatory) for those metabolites that were previously studied are consistent with our findings, suggesting that the well-known immunomodulatory effect of Ganoderma triterpenoids and sterols might be attributed, at least partially, to their ability to act as specific GCR ligands.

Glucocorticoids are amongst the most used drugs to treat retinal diseases of various origins. Yet, the transcriptional regulations induced by glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) activation in retinal pigment epithelium cells (RPE) that form the outer blood–retina barrier are unknown. Levels of endogenous corticoids, ligands for MR and GR, were measured in human ocular media. Human RPE cells derived from induced pluripotent stem cells (iRPE) were used to analyze the pan-transcriptional regulations induced by aldosterone—an MR-specific agonist, or cortisol or cortisol + RU486—a GR antagonist. The retinal phenotype of transgenic mice that overexpress the human MR (P1.hMR) was analyzed. In the human eye, the main ligand for GR and MR is cortisol. The iRPE cells express functional GR and MR. The subset of genes regulated by aldosterone and by cortisol + RU-486, and not by cortisol alone, mimics an imbalance toward MR activation. They are involved in extracellular matrix remodeling (CNN1, MGP, AMTN), epithelial–mesenchymal transition, RPE cell proliferation and migration (ITGB3, PLAUR and FOSL1) and immune balance (TNFSF18 and PTX3). The P1.hMR mice showed choroidal vasodilation, focal alteration of the RPE/choroid interface and migration of RPE cells together with RPE barrier function alteration, similar to human retinal diseases within the pachychoroid spectrum. RPE is a corticosteroid-sensitive epithelium. MR pathway activation in the RPE regulates genes involved in barrier function, extracellular matrix, neural regulation and epithelial differentiation, which could contribute to retinal pathology.

INTRODUCTION AND OBJECTIVE:Abiraterone acetate (AA) has proven survival benefit for patients with metastatic hormone sensitive prostate cancer (mHSPC) and metastatic castrate resistant prostate can...

Primary adrenal insufficiency leads to the decreased production of cortisol and aldosterone. Patients develop an electrolyte imbalance, which can be severe and life-threatening. It is more common in women, usually between the second and fourth decades. We present the case of a 58-year-old female who was admitted due to laboratory findings of severe hyponatremia. Further workup revealed the underlying cause to be primary adrenal insufficiency. Our case report highlights that profound hyponatremia can present with minimal non-specific symptoms and the absence of any neurological manifestations. Correction of hyponatremia, treatment with hydrocortisone and fludrocortisone, and water restriction in the management of this patient resulted in full clinical recovery.

Background Liquorice is found in many food products, soft drinks, and herbal medicines. Liquorice ingestion is an uncommon cause of apparent mineralocorticoid excess or pseudo-aldosteronism. The mechanism involves the inhibition of 11-beta-hydroxysteroid dehydrogenase type-2 by the active ingredient called glycyrrhizin. This leads to the uninhibited activation of mineralocorticoid receptors by cortisol. Confectionary products that contain liquorice are readily available in many countries around the world. Case presentation We report a case of severe refractory hypokalaemia with hypertensive crisis and acute pulmonary oedema due to excessive liquorice consumption. A 79-year-old female presented to the emergency department following a road traffic accident. She described feeling weak and dizzy while driving before the collision. She attended her general practitioner (GP) several weeks earlier for fatigue and was being managed for hypokalaemia on oral potassium supplements. Investigations revealed hypertension (BP 180/69 mmHg), severe hypokalaemia (K 2.2 mmol/l), normal renal function, normal serum magnesium with metabolic alkalosis. Spot urinary potassium was 22 mmol/l. The patient denied taking medications including over-the-counter or herbal medication that can cause hypokalaemia. Hypokalaemia persisted despite aggressive intravenous (i.v.) and oral potassium replacement. She later developed a hypertensive crisis (BP 239/114 mmHg) with pulmonary oedema. She required admission to the intensive care unit and was managed with intravenous furosemide infusion and isosorbide dinitrate infusion. On further discussion, our patient admitted to struggling with nicotine cravings since quitting smoking two months earlier. She began eating an excessive amount of liquorice sweets to manage her cravings. Suppression of plasma renin and aldosterone supported the diagnosis of apparent mineralocorticoid excess secondary to excessive liquorice consumption. Her symptoms and hypokalaemia resolved after stopping liquorice intake. Conclusions This case highlights the life-threatening and refractory nature of hypokalaemia secondary to excessive liquorice consumption. This case also emphasizes the importance of comprehensive history taking including dietary habits. Increased awareness among the public is required regarding the potential health hazards of excessive liquorice consumption.

We developed a sensitive method for monitoring six natural (aldosterone) and synthetic mineralocorticoids (canrenone, spironolactone, 7β-spironolactone, 7α-thio spironolactone, and 7α-thiomethyl spironolactone) in sediment and water using ultra-performance liquid chromatography–electrospray tandem mass spectrometry, and then 30 water and 30 sediment samples were analyzed to reveal their occurrence and distributions in Taihu Lake. All target six mineralocorticoids were detected in sediment and water samples with the detection frequencies as high as 96–100%. The median concentrations of mineralocorticoids ranged from 0.04 ng/L (7α-thiomethyl spironolactone) to 14 ng/L (aldosterone) in water and 0.01 ng/g (7β-spironolactone and canrenone) to 1.44 ng/g (aldosterone) in sediment in dry weight. Natural aldosterone was the predominant mineralocorticoid detected in both water and sediment samples, indicating the mineralocorticoid pollution in Taihu Lake was mainly derived from human and/or animal excrement rather than pharmaceutical industry and usage. Two metabolites 7β-spironolactone and 7α-thio spironolactone were first found in this study. Low ratios of metabolites to spironolactone were observed in sediment (0.05–0.75) in contrast to water (0.12–2.26), indicating that spironolactone was prone to degradation in water phase compared to sediment environment.

Mineralocorticoids (e.g., aldosterone) support chronic inflammatory tissue damage, including glomerular mesangial injury leading to glomerulosclerosis. Furthermore, aldosterone leads to activation of the extracellular signal-regulated kinases (ERK1/2) in rat glomerular mesangial cells (GMC). Because ERK1/2 can affect cellular pH homeostasis via activation of Na+/H+-exchange (NHE) and the resulting cellular alkalinization may support proliferation, we tested the hypothesis that aldosterone affects pH homeostasis and thereby cell proliferation as well as collagen secretion also in primary rat GMC. Cytoplasmic pH and calcium were assessed by single-cell fluorescence ratio imaging, using the dyes BCECF or FURA2, respectively. Proliferation was determined by cell counting, thymidine incorporation and collagen secretion by collagenase-sensitive proline incorporation and ERK1/2-phosphorylation by Western blot. Nanomolar aldosterone induces a rapid cytosolic alkalinization which is prevented by NHE inhibition (10 µmol/L EIPA) and by blockade of the mineralocorticoid receptor (100 nmol/L spironolactone). pH changes were not affected by inhibition of HCO3− transporters and were not dependent on HCO3−. Aldosterone enhanced ERK1/2 phosphorylation and inhibition of ERK1/2-phosphorylation (10 µmol/L U0126) prevented aldosterone-induced alkalinization. Furthermore, aldosterone induced proliferation of GMC and collagen secretion, both of which were prevented by U0126 and EIPA. Cytosolic calcium was not involved in this aldosterone action. In conclusion, our data show that aldosterone can induce GMC proliferation via a MR and ERK1/2-mediated activation of NHE with subsequent cytosolic alkalinization. GMC proliferation leads to glomerular hypercellularity and dysfunction. This effect presents a possible mechanism contributing to mineralocorticoid receptor-induced pathogenesis of glomerular mesangial injury during chronic kidney disease.

Individuals with type 2 diabetes have an increased risk of cardiovascular disease. A correlation between plasma aldosterone and hyperinsulinemia has been demonstrated in vivo, and hyperinsulinemia and insulin resistance are independently associated with the development of cardiovascular complications. We investigated if mineralocorticoid blockade (Eplerenone) improves insulin sensitivity in individuals with type 2 diabetes compared to healthy controls. We included 13 participants with type 2 diabetes (, Individuals with type 2 diabetes have an increased risk of developing cardiovascular complications and a correlation between plasma aldosterone and hyperinsulinemia has been shown in vivo. Despite this, the present study does not show a beneficial effect of blockade of the mineralocorticoid receptor in individuals with type 2 diabetes compared to healthy controls.

The therapeutic indices (TIs) and efficacy of the non-steroidal mineralocorticoid receptor antagonist (MRA) KBP-5074 and steroidal MRA eplerenone were evaluated in a uninephrectomized Sprague Dawley rat model of aldosterone-mediated renal disease. In two parallel studies, rats were placed on a high-salt diet and received aldosterone by osmotic mini-pump infusion over the course of 27 days. The urinary albumin-to-creatinine ratio (UACR) was evaluated after 7, 14, and 26 days of treatment. Serum K+ was evaluated after 14 and 27 days of treatment. Urinary Na+, urinary K+, and urinary Na+/K+ ratio were evaluated after 7, 14, and 26 days of treatment. The TI was calculated for each drug as the ratio of the concentration of drug producing 50% of maximum effect (EC50) for increasing serum K+ to the EC50 for lowering UACR. The TIs were 24.5 for KBP-5074 and 0.620 for eplerenone, resulting in a 39-fold improved TI for KBP-5074 compared with eplerenone. Aldosterone treatment increased UACR, decreased serum K+, and decreased urinary Na+ relative to sham-operated controls that did not receive aldosterone infusion in both studies, validating the aldosterone/salt renal injury model. KBP-5074 prevented the increase in UACR at 0.5, 1.5, and 5 mg/kg BID while eplerenone did so only at the two highest doses of 50 and 450 mg/kg BID. Both KBP-5074 and eplerenone blunted the reduction in serum K+ seen in the aldosterone treatment group, with significant increases in serum K+ at the high doses only (5 mg/kg and 450 mg/kg BID, respectively). Additionally, the urinary Na+ and Na+/K+ ratio significantly increased at the middle and high doses of KBP-5074, but only at the highest dose of eplerenone. These results showed increased TI and efficacy for KBP-5074 compared with eplerenone over a wider therapeutic window.

Pulmonary hypertension (PH) is a devastating condition characterized by pulmonary vascular remodelling, leading to progressive increase in pulmonary artery pressure and subsequent right ventricular failure. Aldosterone and the mineralocorticoid receptor (MR), a nuclear transcription factor, are key drivers of cardiovascular disease and MR antagonists are well-established in heart failure. Now, a growing body of evidence points at a detrimental role of MR in PH. Pharmacological MR blockade attenuated PH and prevented RV failure in experimental models. Mouse models with cell selective MR deletion suggest that this effect is mediated by MR in endothelial cells. While the evidence from experimental studies appears convincing, the available clinical data on MR antagonist use in patients with PH is more controversial. Integrated analysis of clinical data together with MR-dependent molecular alterations may provide insights why some patients respond to MRA treatment while others do not. Potential ways to identify MRA ‘responders’ include the analysis of underlying PH causes, stage of disease, or sex, as well as new biomarkers.

A distinct mineralocorticoid receptor (MR) ortholog first appears in cartilaginous fishes, such as sharks, skates, rays and chimaeras. Although aldosterone, the main physiological mineralocorticoid in humans and other terrestrial vertebrates, is a transcriptional activator of skate MR and elephant shark MR, aldosterone is not synthesized by cartilaginous fishes. Aldosterone, first appears in lungfish, which are lobe-finned fish that are forerunners of terrestrial vertebrates. Aldosterone activation of the MR regulates internal homeostasis of water, sodium and potassium, which was critical in the conquest of land by vertebrates. We studied transcriptional activation of the slender African lungfish (Protopterus dolloi) MR by aldosterone, other corticosteroids and progesterone and find that aldosterone, 11-deoxycorticosterone, 11-deoxycortisol and progesterone have half-maximal responses (EC50s) below 1 nM and are potential physiological mineralocorticoids. In contrast, EC50s for corticosterone and cortisol were 23 nM and 66 nM, respectively. Unexpectedly, truncated lungfish MR, consisting of the DNA-binding domain, hinge domain and steroid-binding domain, had a stronger response to aldosterone, other corticosteroids and progesterone than did full-length lungfish MR, indicating that an allosteric action of the N-terminal domain represses steroid activation of lungfish MR. This contrasts to human MR in which the N-terminal domain contains an activation function. BLAST searches of GenBank did not retrieve a GR ortholog, leading us to test dexamethasone and triamcinolone for activation of lungfish MR. At 10 nM, both synthetic glucocorticoids are about 4-fold stronger than 10 nM aldosterone in activating full-length lungfish MR, leading us to propose that lungfish MR also functions as a GR.

Type IV renal tubular acidosis (RTA) is the only RTA characterized by hyperkalemia, and it is caused by a true aldosterone deficiency or renal tubular aldosterone hyporesponsiveness. It is frequent among hospitalized patients as it is related to type 2 diabetes mellitus (T2DM) and common medications such as ACE-inhibitors (ACE-is) and trimethoprim-sulfamethoxazole (TMP-SMX). Drug-induced RTA commonly manifests in patients with predisposing conditions such as mild renal insufficiency and certain pharmacological therapies. ACE-i use and chronic adrenal insufficiency (cAI) are other significant risk factors. Chronic ACTH suppression is thought to induce global adrenal atrophy, including the zona glomerulosa, thus affecting aldosterone secretion as well. Furthermore, in the setting of cAI, treatment with ACE-is further suppresses aldosterone production. This case report describes a patient with cAI secondary to corticosteroid use for years who developed type IV RTA in the setting of lisinopril use. Potassium (K) elevation persisted despite removing underlying conditions and metabolic acidosis correction. The patient required long-term treatment with mineralocorticoids in addition to sodium bicarbonate to maintain normal K levels and acid-base status. Mineralocorticoid administration is a second-line treatment for type IV RTA, but it might be necessary for a subgroup of high-risk patients. In fact, it is important to consider patients with chronic adrenal insufficiency and on ACE-is treatment at increased risk for refractory hyperkalemia in the setting of type IV RTA. Indeed, this subgroup of patients can have severe hypoaldosteronism.

The mineralocorticoid aldosterone is produced in the adrenal zona glomerulosa (ZG) under the control of the renin–angiotensin II (AngII) system. Primary aldosteronism (PA) results from renin-independent production of aldosterone and is a common cause of hypertension. PA is caused by dysregulated localization of the enzyme aldosterone synthase (Cyp11b2), which is normally restricted to the ZG. Cyp11b2 transcription and aldosterone production are predominantly regulated by AngII activation of the Gq signaling pathway. Here, we report the generation of transgenic mice with Gq-coupled designer receptors exclusively activated by designer drugs (DREADDs) specifically in the adrenal cortex. We show that adrenal-wide ligand activation of Gq DREADD receptors triggered disorganization of adrenal functional zonation, with induction of Cyp11b2 in glucocorticoid-producing zona fasciculata cells. This result was consistent with increased renin-independent aldosterone production and hypertension. All parameters were reversible following termination of DREADD-mediated Gq signaling. These findings demonstrate that Gq signaling is sufficient for adrenocortical aldosterone production and implicate this pathway in the determination of zone-specific steroid production within the adrenal cortex. This transgenic mouse also provides an inducible and reversible model of hyperaldosteronism to investigate PA therapeutics and the mechanisms leading to the damaging effects of aldosterone on the cardiovascular system.

BACKGROUND AND PURPOSE: Aldosterone stimulates epithelial Na(+) channel (ENaC)‐dependent Na(+) retention in the cortical collecting duct (CCD) of the kidney by activating mineralocorticoid receptors that promote expression of serum and glucocorticoid‐inducible kinase 1 (SGK1). This response is critical to BP homeostasis. It has previously been suggested that inhibiting lysine deacetylases (KDACs) can post‐transcriptionally disrupt this response by promoting acetylation of the mineralocorticoid receptor. The present study critically evaluates this hypothesis. EXPERIMENTAL APPROACH: Electrometric and molecular methods were used to define the effects of a pan‐KDAC inhibitor, trichostatin A, on the responses to a physiologically relevant concentration of aldosterone (3 nM) in murine mCCD(cl1) cells. KEY RESULTS: Aldosterone augmented ENaC‐induced Na(+) absorption and increased SGK1 activity and abundance, as expected. In the presence of trichostatin A, these responses were suppressed. Trichostatin A‐induced inhibition of KDAC was confirmed by increased acetylation of histone H3, H4, and α‐tubulin. Trichostatin A did not block the electrometric response to insulin, a hormone that activates SGK1 independently of increased transcription, indicating that trichostatin A has no direct effect upon the SGK1/ENaC pathway. CONCLUSIONS AND IMPLICATIONS: Inhibition of lysine de‐acetylation suppresses aldosterone‐dependent control over the SGK1–ENaC pathway but does not perturb post‐transcriptional signalling, providing a physiological basis for the anti‐hypertensive action of KDAC inhibition seen in vivo.

We have recently reported that type A intercalated cells of the collecting duct secrete Na+ by a mechanism coupling the basolateral type 1 Na+-K+-2Cl− cotransporter with apical type 2 H+-K+-ATPase (HKA2) functioning under its Na+/K+ exchange mode. The first aim of the present study was to evaluate whether this secretory pathway is a target of atrial natriuretic peptide (ANP). Despite hyperaldosteronemia, metabolic acidosis is not associated with Na+ retention. The second aim of the present study was to evaluate whether ANP-induced stimulation of Na+ secretion by type A intercalated cells might account for mineralocorticoid escape during metabolic acidosis. In Xenopus oocytes expressing HKA2, cGMP, the second messenger of ANP, increased the membrane expression, activity, and Na+-transporting rate of HKA2. Feeding mice with a NH4Cl-enriched diet increased urinary excretion of aldosterone and induced a transient Na+ retention that reversed within 3 days. At that time, expression of ANP mRNA in the collecting duct and urinary excretion of cGMP were increased. Reversion of Na+ retention was prevented by treatment with an inhibitor of ANP receptors and was absent in HKA2-null mice. In conclusion, paracrine stimulation of HKA2 by ANP is responsible for the escape of the Na+-retaining effect of aldosterone during metabolic acidosis.

Human cytochrome P450 (P450) 11B2 catalyzes the formation of aldosterone, the major endogenous human mineralocorticoid. Aldosterone is important for the regulation of electrolyte homeostasis. Mutations and overexpression of P450 11B2 (also known as aldosterone synthase) can lead to hypertension, congestive heart failure, and diabetic nephropathy. The enzyme is therefore a target for drug development to manage these various disorders. P450 11B2 catalyzes aldosterone formation from 11-deoxycorticosterone through three distinct oxidation steps. It is currently unknown to which degree these reactions happen in sequence without the intermediate products dissociating from the enzyme (i.e. processively) or whether these reactions happen solely distributively, in which the intermediate products must first dissociate and then rebind to the enzyme before subsequent oxidation. We present here a comprehensive investigation of processivity in P450 11B2–catalyzed reactions using steady-state, pre-steady–state, pulse-chase, equilibrium-binding titrations, and stopped-flow binding studies. We utilized the data obtained to develop a kinetic model for P450 11B2 and tested this model by enzyme kinetics simulations. We found that although aldosterone is produced processively, the enzyme preferentially utilizes a distributive mechanism that ends with the production of 18-OH corticosterone. This seemingly contradictory observation could be resolved by considering the ability of the intermediate product 18-OH corticosterone to exist as a lactol form, with the equilibrium favoring the ring-closed lactol configuration. In summary, our refined model for P450 11B2 catalysis indicates isomerization of the intermediate to a lactol can explain why P450 11B2 must produce aldosterone through a processive mechanism despite favoring a distributive mechanism.

The early postnatal period is critical for the development of the nervous system. Stress during this period causes negative long-term effects, which are manifested at both behavioral and molecular levels. To simulate the elevated glucocorticoid levels characteristic of early-life stress, in our study we used the administration of dexamethasone, an agonist of glucocorticoid receptors, at decreasing doses at the first three days of life (0.5, 0.3, 0.1 mg/kg, s.c.). In adult male mice with neonatal dexamethasone treatment, an increase in the relative weight of the adrenal glands and a decrease in body weight were observed, while the basal level of corticosterone remained unchanged. Dexamethasone treatment in early life had a negative impact on the learning and spatial memory of adult mice in the Morris water maze. We analyzed the effect of elevated glucocorticoid levels in early life on the expression of the Crh, Avp, Gr, and Mr genes involved in the regulation of the HPA axis in the hypothalami of adult mice. The expression level of the mineralocorticoid receptor gene (Mr) was significantly downregulated, and the glucocorticoid receptor gene (Gr) showed a tendency towards decreased expression (p = 0.058) in male mice neonatally treated with dexamethasone, as compared with saline administration. The expression level of the Crh gene encoding corticotropin-releasing hormone was unchanged, while the expression of the vasopressin gene (Avp) was increased in response to neonatal administration of dexamethasone. The obtained results demonstrate a disruption of negative feedback regulation of the HPA axis, which involves glucocorticoid and mineralocorticoid receptors, at the level of the hypothalamus. Malfunction of the HPA axis as a result of activation of the glucocorticoid system in early life may cause the development of cognitive impairment in the adult mice.

We describe two cases of hypertension and hypokalemia due to mineralocorticoid excess caused by posaconazole treatment of coccidioidomycosis and rhinocerebral mucormycosis infections, respectively. Clinical laboratory evaluations, including a comprehensive analysis of blood and urine steroid profiles, revealed low renin and aldosterone and indicated as the underlying mechanism primarily a block of 11β-hydroxylase activity in patient 1, whereas patient 2 displayed weaker 11β-hydroxylase but more pronounced 11β-hydroxysteroid dehydrogenase 2 inhibition. The results show that both previously suggested mechanisms must be considered and emphasize significant interindividual differences in the contribution of each enzyme to the observed mineralocorticoid excess phenotype. The mineralocorticoid symptoms of patient 1 resolved after replacement of posaconazole therapy by isavoconazole, and posaconazole dosage de-escalation ameliorated the effects in patient 2. By providing a thorough analysis of the patients’ blood and urine steroid metabolites, this report adds further evidence for two individually pronounced mechanisms of posaconazole-induced hypertension and hypokalemia. The elucidation of the factors responsible for the individual phenotype warrants further research.

Objective Analysis of steroids by gas chromatography-mass spectrometry (GC-MS) defines a subject’s steroidal fingerprint. Here, we compare the steroidal fingerprints of obese children with or without liver disease to identify the ‘steroid metabolomic signature’ of childhood nonalcoholic fatty liver disease. Methods Urinary samples of 85 children aged 8.5–18.0 years with BMI >97% were quantified for 31 steroid metabolites by GC-MS. The fingerprints of 21 children with liver disease (L1) as assessed by sonographic steatosis (L1L), elevated alanine aminotransferases (L1A) or both (L1AL), were compared to 64 children without markers of liver disease (L0). The steroidal signature of the liver disease was generated as the difference in profiles of L1 against L0 groups. Results L1 comparing to L0 presented higher fasting triglycerides (P = 0.004), insulin (P = 0.002), INS/GLU (P = 0.003), HOMA-IR (P = 0.002), GGTP (P = 0.006), AST/SGOT (P = 0.002), postprandial glucose (P = 0.001) and insulin (P = 0.011). L1AL showed highest level of T-cholesterol and triglycerides (P = 0.029; P = 0.044). Fasting insulin, postprandial glucose, INS/GLU and HOMA-IR were highest in L1L and L1AL (P = 0.001; P = 0.017; P = 0.001; P = 0.001). The liver disease steroidal signature was marked by lower DHEA and its metabolites, higher glucocorticoids (mostly tetrahydrocortisone) and lower mineralocorticoid metabolites than L0. L1 patients showed higher 5α-reductase and 21-hydroxylase activity (the highest in L1A and L1AL) and lower activity of 11βHSD1 than L0 (P = 0.041, P = 0.009, P = 0.019). Conclusions The ‘steroid metabolomic signature’ of liver disease in childhood obesity provides a new approach to the diagnosis and further understanding of its metabolic consequences. It reflects the derangements of steroid metabolism in NAFLD that includes enhanced glucocorticoids and deranged androgens and mineralocorticoids.

Mineralocorticoid hypertension is most often caused by autonomous overproduction of aldosterone, but excess of other mineralocorticoid precursors can lead to a similar presentation. 11-Deoxycorticosterone (DOC) excess, which can occur in 11-β hydroxylase or 17-α hydroxylase deficiencies, in DOC-producing adrenocortical tumours or in patients taking 11-β hydroxylase inhibitors, may cause mineralocorticoid hypertension. We report a 35-year-old woman who in the third trimester of pregnancy was found to have a large adrenal mass on routine obstetric ultrasound. On referral to our unit, persistent hypertension and long-standing hypokalaemia was noted, despite good compliance with multiple antihypertensives. Ten years earlier, she had hypertension noted in pregnancy which had persisted after delivery. A MRI scan confirmed the presence of a 12 cm adrenal mass and biochemistry revealed high levels of DOC and low/normal renin, aldosterone and dehydroepiandrosterone, with normal catecholamine levels. The patient was treated with antihypertensives until obstetric delivery, following which she underwent an adrenalectomy. Histology confirmed a large adrenal cortical neoplasm of uncertain malignant potential. Postoperatively, blood pressure and serum potassium normalised, and the antihypertensive medication was stopped. Over 10 years of follow-up, she remains asymptomatic with normal DOC measurements. This case should alert clinicians to the possibility of a diagnosis of a DOC-producing adrenal tumours in patients with adrenal nodules and apparent mineralocorticoid hypertension in the presence of low or normal levels of aldosterone. The associated diagnostic and management challenges are discussed. Learning points: Hypermineralocorticoidism is characterised by hypertension, volume expansion and hypokalaemic alkalosis and is most commonly due to overproduction of aldosterone. However, excess of other mineralocorticoid products, such as DOC, lead to the same syndrome but with normal or low aldosterone levels. The differential diagnosis of resistant hypertension with low renin and low/normal aldosterone includes congenital adrenal hyperplasia, syndrome of apparent mineralocorticoid excess, Cushing’s syndrome, Liddle’s syndrome and 11-deoxycorticosterone-producing tumours. DOC is one intermediate product in the mineralocorticoid synthesis with weaker activity than aldosterone. However, marked DOC excess seen in 11-β hydroxylase or 17-α hydroxylase deficiencies in DOC-producing adrenocortical tumours or in patients taking 11-β hydroxylase inhibitors, may cause mineralocorticoid hypertension. Excessive production of DOC in adrenocortical tumours has been attributed to reduced activity of the enzymes 11-β hydroxylase and 17-α hydroxylase and increased activity of 21-α hydroxylase. The diagnosis of DOC-producing adrenal tumours is challenging because of its rarity and poor availability of DOC laboratory assays. Background Mineralocorticoid-induced hypertension is common and normally associated with autonomous aldosterone overproduction (primary hyperaldosteronism). However, other mineralocorticoid hormones such 11-deoxycorticosterone (DOC) may be responsible for a similar condition (1, 2). The rarity of DOC-producing adrenocortical tumours (3) and poor availability of laboratory assays to measure mineralocorticoid products other than aldosterone cause diagnostic challenges. This case highlights the diagnostic challenges, with the patient’s diagnosis remaining hidden for at least 10 years.

The recent advances in genetics and molecular biology have resulted in the characterization of key components that critically regulate renal NaCl transport and blood pressure. Pendrin is a Cl−/HCO3− exchanger that is highly expressed in thyroid, inner ear, and kidney. In the kidney, it is selectively present at the apical membrane in non-α intercalated cells of the connecting tubules and cortical collecting duct. Besides its role in acid/base homeostasis, accumulating studies using various genetically modified animals have provided compelling evidence that pendrin regulates extracellular fluid volume and electrolyte balance at the downstream of aldosterone signaling. We have shown that angiotensin II and aldosterone cooperatively control pendrin abundance partly through mammalian target of rapamycin signaling and mineralocorticoid receptor dephosphorylation, which is necessary for the kidney to prevent extracellular fluid loss and electrolyte disturbances under physiologic perturbations. In line with the experimental observations, several clinical data indicated that the impaired pendrin function can cause fluid and electrolyte abnormalities in humans. The purpose of this review is to provide an update on the recent progress regarding the role of pendrin in fluid and electrolyte homeostasis, as well as in the pathophysiology of hypertension associated with mineralocorticoid receptor signaling.