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We identified five distinct full-length human mineralocorticoid receptor (MR) genes containing either 984 amino acids (MR-984) or 988 amino acids (MR-988), which can be distinguished by the presence or absence of Lys, Cys, Ser, and Trp (KCSW) in their DNA-binding domain (DBD) and mutations at codons 180 and 241 in their amino-terminal domain (NTD). Two human MR-KCSW genes contain either (Val-180, Val-241) or (Ile-180, Val-241) in their NTD, and three human MR-984 genes contain either (Ile-180, Ala-241), (Val-180, Val-241), or (Ile-180, Val-241). Human MR-KCSW with (Ile-180, Ala-241) has not been cloned. In contrast, chimpanzees contain four MRs: two MR-988s with KCSW in their DBD, or two MR-984s without KCSW in their DBD. Chimpanzee MRs only contain (Ile180, Val-241) in their NTD. A chimpanzee MR with either (Val-180, Val-241) or (Ile-180, Ala-241) in the NTD has not been cloned. Gorillas and orangutans each contain one MR-988 with KCSW in the DBD and one MR-984 without KCSW, and these MRs only contain (Ile-180, Val-241) in their NTD. A gorilla MR or orangutan MR with either (Val-180, Val-241) or (Ile-180, Ala-241) in the NTD has not been cloned. Together, these data suggest that human MRs with (Val-180, Val-241) or (Ile-180, Ala-241) in the NTD evolved after humans and chimpanzees diverged from their common ancestor. Considering the multiple functions in human development of the MR in kidney, brain, heart, skin, and lungs, as well as MR activity in interaction with the glucocorticoid receptor, we suggest that the evolution of human MRs that are absent in chimpanzees may have been important in the evolution of humans from chimpanzees. Investigation of the physiological responses to corticosteroids mediated by the MR in humans, chimpanzees, gorillas, and orangutans may provide insights into the evolution of humans and their closest relatives. [ABSTRACT FROM AUTHOR]

The immunotropic effects of aldosterone might play a role in COVID-19, as SARS-CoV-2 reportedly uses angiotensin-converting enzyme 2 receptors as an entry point into cells. Aldosterone function is closely linked to its action on mineralocorticoid receptors in kidneys; it increases the renal retention of sodium and the excretion of potassium, which increases blood pressure. Despite the large number of studies examining the effect of Ang-II and its blockers on the course of COVID-19 infection, there is still uncertainty about the role of aldosterone. The aim of the study was to assess the correlation of aldosterone, urea, creatinine, C-reactive protein (CRP), and procalcitonin (PCT) levels with 28 days of mortality in patients treated for COVID19 in an intensive care unit (ICU). This cross-selection study involved 115 adult patients who were divided into two groups: those who died within a 28-day period (n = 82) and those who survived (n = 33). The correlation of aldosterone, urea, creatinine, C-reactive protein (CRP), and procalcitonin (PCT) levels with 28 days of mortality in patients treated for COVID-19 were performed. The patients' age, sex, scores from the APACHE II, SAPS II, and SOFA scales and comorbidities like HA, IHD and DM were also analyzed. Remarkably, the individuals who survived for 28 days were of significantly lower mean age and achieved notably lower scores on the APACHE II, SAPS II, and SOFA assessment scales. Statistically significantly higher CRP levels were observed on days 3, 5, and 7 in individuals who survived for 28 days. Creatinine levels in the same group were also statistically significantly lower on days 1, 3, and 5 than those of individuals who died within 28 days. The investigation employed both univariate and multivariate Cox proportional hazard regression models to explore factors related to mortality. In the univariate analysis, variables with a p value of less than 0.50 were included in the multivariate model. Age, APACHE II, SAPS II, and SOFA demonstrated significance in univariate analysis and were considered to be associated with mortality. The outcomes of the multivariate analysis indicated that age (HR = 1.03, p = 0.033) served as a robust predictor of mortality in the entire study population. In conclusion the plasma aldosterone level is not associated with ICU mortality in patients with COVID-19. Other factors, including the patient's age, creatinine or CRP contribute to the severity and prognosis of the disease. This study was retrospectively registered in the Australian New Zealand Clinical Trials Registry (ANZCTR) with registration no. ACTRN12621001300864 (27/09/2021: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=382563&isReview=true). [ABSTRACT FROM AUTHOR]

Aldosterone has been suggested to be involved in the microvascular complications observed in type 2 diabetes. We aimed to investigate the effect of mineralocorticoid receptor (MR) blockade on endothelial function in individuals with type 2 diabetes compared to healthy controls. We included 12 participants with type 2 diabetes and 14 controls. We measured leg hemodynamics at baseline and during femoral arterial infusion of acetylcholine and sodium nitroprusside before and 8 weeks into treatment with MR blockade (eplerenone). Acetylcholine infusion was repeated with concomitant n‐acetylcysteine (antioxidant) infusion. No difference in leg blood flow or vascular conductance was detected before or after the treatment with MR blockade in both groups and there was no difference between groups. Infusion of n‐acetylcysteine increased baseline blood flow and vascular conductance, but did not change the vascular response to acetylcholine before or after treatment with MR blockade. Skeletal muscle eNOS content was unaltered by MR blockade and no difference between groups was detected. In conclusion, we found no effect of MR blockade endothelial function in individuals with and without type 2 diabetes. As the individuals with type 2 diabetes did not have vascular dysfunction, these results might not apply to individuals with vascular dysfunction. [ABSTRACT FROM AUTHOR]

Modulation of the renin-angiotensin-aldosterone system is a foundation of therapy for cardiovascular and kidney diseases. Excess aldosterone plays an important role in cardiovascular disease, contributing to inflammation, fibrosis, and dysfunction in the heart, kidneys, and vasculature through both genomic and mineralocorticoid receptor (MR)-mediated as well as nongenomic mechanisms. MR antagonists have been a key therapy for attenuating the pathologic effects of aldosterone but are associated with some side effects and may not always adequately attenuate the nongenomic effects of aldosterone. Aldosterone is primarily synthesized by the CYP11B2 aldosterone synthase enzyme, which is very similar in structure to other enzymes involved in steroid biosynthesis including CYP11B1, a key enzyme involved in glucocorticoid production. Lack of specificity for CYP11B2, off-target effects on the hypothalamic-pituitary-adrenal axis, and counterproductive increased levels of bioactive steroid intermediates such as 11-deoxycorticosterone have posed challenges in the development of early aldosterone synthase inhibitors such as osilodrostat. In early-phase clinical trials, newer aldosterone synthase inhibitors demonstrated promise in lowering blood pressure in patients with treatment-resistant and uncontrolled hypertension. It is therefore plausible that these agents offer protection in other disease states including heart failure or chronic kidney disease. Further clinical evaluation will be needed to clarify the role of aldosterone synthase inhibitors, a promising class of agents that represent a potentially major therapeutic advance. [ABSTRACT FROM AUTHOR]

Diabetic Kidney Disease (DKD) is a significant complication of diabetes and primary cause of end-stage renal disease globally. The exact mechanisms underlying DKD remain poorly understood, but multiple factors, including the renin–angiotensin–aldosterone system (RAAS), play a key role in its progression. Aldosterone, a mineralocorticoid steroid hormone, is one of the key components of RAAS and a potential mediator of renal damage and inflammation in DKD. miRNAs, small noncoding RNA molecules, have attracted interest due to their regulatory roles in numerous biological processes. These processes include aldosterone signaling and mineralocorticoid receptor (MR) expression. Numerous miRNAs have been recognized as crucial regulators of aldosterone signaling and MR expression. These miRNAs affect different aspects of the RAAS pathway and subsequent molecular processes, which impact sodium balance, ion transport, and fibrosis regulation. This review investigates the regulatory roles of particular miRNAs in modulating aldosterone signaling and MR activation, focusing on their impact on kidney injury, inflammation, and fibrosis. Understanding the complex interaction between miRNAs and the RAAS could lead to a new strategy to target aldosterone signaling and MR activation using miRNAs. This highlights the potential of miRNA-based interventions for DKD, with the aim of enhancing kidney outcomes in individuals with diabetes. [ABSTRACT FROM AUTHOR]

Aldosterone (Aldo) exerts its action through binding with the mineralocorticoid receptor (MR). Clinically, a link between primary aldosteronism (PA) and thyroid diseases has been hypothesised. However, the presence and activity of MR on the thyroid have not yet been demonstrated. We investigated the gene/protein expression and activation of MR in primary thyroid cell cultures (normal rat thyroid [FRTL-5] and human papillary thyroid cancer [PTC] cell lines, BCPAP and K1) through qRT-PCR analysis, immunofluorescence, and confocal microscopy. We also studied the effects of Aldo on thyroid-specific and inflammation genes in vitro. Paired human normal and neoplastic thyroid tissues were also studied. We demonstrated both gene and protein expression and activation of MR in normal rat thyroid and human PTC lines. Incubation with Aldo induced an acute increase in IL-6 expression in both the FRTL-5 and BCPAP lines, which was antagonised by spironolactone, and an acute and late upregulation of thyroid-specific genes in FRTL-5. MR was also expressed at both gene and protein levels in normal human thyroid tissues and in PTC, with a progressive decline during neoplastic tumourigenesis, particularly in more aggressive histotypes. We present the first evidence of MR gene and protein expression in both normal and pathological thyroid cells and tissues. We have shown that MR is present and functionally activated in thyroid tissue. Binding of Aldo to MR induces the expression of inflammatory and thyroid-specific genes, and the thyroid may thus be considered a novel mineralocorticoid target tissue. [ABSTRACT FROM AUTHOR]

Hypertension is a critical component of cardiovascular disease progression in patients with chronic kidney disease, and specifically diabetic kidney disease (DKD). Causation versus correlation remains up for debate, but what has been confirmed is the delay of DKD progression when hypertension is controlled or moved to guideline drive ranges. Many medications have been studied and used in real world experience for best outcomes, and we discuss below the proven winners thus far making up the renin angiotensin aldosterone system. As well, we discuss guideline changing medications including sodium-glucose cotransporter 2 inhibitors and newer generation mineralocorticoid receptor antagonists. With the growing prevalence of diabetes and DKD in the population, newer agents are emerging in multiple drug class and will be highlighted below. Clinicians continue to search for the optimal care plans for this challenging patient population. [ABSTRACT FROM AUTHOR]

Primary aldosteronism, or Conn syndrome, is the most common endocrine cause of hypertension. It is associated with a higher risk of cardiovascular, metabolic and renal diseases, as well as a lower quality of life than for hypertension due to other causes. The multi-systemic effects of primary aldosteronism can be attri buted to aldosteronemediated activation of the mineralocorticoid receptor in a range of tissues. In this review, we explore the signalling pathways of the mineralocorticoid receptor, with a shift from the traditional focus on the regulation of renal sodium-potassium exchange to a broader understanding of its role in the modulation of tissue i nflammation, fibrosis and remodelling. The appreciation of primary aldosteronism as a multi-system disease with tissue-specific pathophysiology may lead to more vigilant testin g and earlier institution of targeted interventions. [ABSTRACT FROM AUTHOR]

Renal fibrosis is an inevitable process in the progression of chronic kidney disease (CKD). Angiogenesis plays an important role in this process. Vascular endothelial cells are involved in renal fibrosis by phenotypic transformation and secretion of extracellular matrix. Aldosterone stimulates mineralocorticoid receptor (MR) activation and induces inflammation, which is important for angiogenesis. Clinically, MR blockers (MRBs) have a protective effect on damaged kidneys, which may be associated with inhibition of angiogenesis. In this study, we used aldosterone-infused mice and found that aldosterone induced angiogenesis and that endothelial-mesenchymal transition (EndMT) in neovascular endothelial cells was involved in renal fibrosis. Notably, aldosterone induced inflammation and stimulated macrophages to secrete vascular endothelial growth factor (VEGF) A to regulate angiogenesis by activating MR, whereas EndMT occurred in response to transforming growth factor-β1 (TGF-β1) induction and participated in renal fibrosis. These effects were antagonized by the MRB esaxerenone. These findings suggest that reducing angiogenesis may be an effective strategy for treating renal fibrosis. [ABSTRACT FROM AUTHOR]

Background: Primary aldosteronism (PA) is a frequent cause of hypertension. Aldosterone excess together with high dietary salt intake aggravates cardiovascular damage, despite guideline‐recommended mineralocorticoid receptor antagonist (MRA) treatment. Objectives: To investigate the antihypertensive impact of a moderate dietary salt restriction and associated physiological changes, including mental well‐being. Methods: A total of 41 patients with PA on a stable antihypertensive regimen—including MRA—followed a dietary salt restriction for 12 weeks with structured nutritional training and consolidation by a mobile health app. Salt intake and adherence were monitored every 4 weeks using 24‐h urinary sodium excretion and nutrition protocols. Body composition was assessed by bioimpedance analysis and mental well‐being by validated questionnaires. Results: Dietary salt intake significantly decreased from 9.1 to 5.2 g/d at the end of the study. In parallel, systolic (130 vs. 121 mm Hg) and diastolic blood pressure (BP) (84 vs. 81 mm Hg) improved significantly. Patients' aptitude of estimating dietary salt content was refined significantly (underestimation by 2.4 vs. 1.4 g/d). Salt restriction entailed a significant weight loss of 1.4 kg, improvement in pulse pressure (46 vs. 40 mm Hg) and normalization of depressive symptoms (PHQD scale, p < 0.05). Salt restriction, cortisol after dexamethasone suppression test and dosage of renin‐angiotensin‐aldosterone‐system (RAAS) blockers were independently associated with BP reduction. Conclusion: A moderate restriction of dietary salt intake in patients with PA substantially reduces BP and depressive symptoms. Moreover, the findings underline that a sufficient RAAS blockade seems to augment the effects of salt restriction on BP and cardiovascular risk. [ABSTRACT FROM AUTHOR]

The renin angiotensin aldosterone system is a key regulator of blood pressure. Aldosterone is the final effector of this pathway, acting predominantly via mineralocorticoid receptors. Aldosterone facilitates the conservation of sodium and, with it, water and acts as a powerful stimulus for potassium excretion. However, evidence for the pathological impact of excess mineralocorticoid receptor stimulation is increasing. Here, we discussed how in the heart, hyperaldosteronism is associated with fibrosis, cardiac dysfunction, and maladaptive hypertrophy. In the kidney, aldosterone was shown to cause proteinuria and fibrosis and may contribute to the progression of kidney disease. More recently, studies suggested that aldosterone excess damaged endothelial cells. Here, we reviewed how damage to the endothelial glycocalyx may contribute to this process. The endothelial glycocalyx is a heterogenous, negatively charged layer on the luminal surface of cells. Aldosterone exposure alters this layer. The resulting structural changes reduced endothelial reactivity in response to protective shear stress, altered permeability, and increased immune cell trafficking. Finally, we reviewed current therapeutic strategies for limiting endothelial damage and suggested that preventing glycocalyx remodelling in response to aldosterone exposure may provide a novel strategy, free from the serious adverse effect of hyperkalaemia seen in response to mineralocorticoid blockade. [ABSTRACT FROM AUTHOR]

Renal ischemia reperfusion (IR) injury is a major cause of acute kidney injury (AKI) that is often complicated by multiple organ failure of the liver and intestine. The mineralocorticoid receptor (MR) is activated in patients with renal failure associated with glomerular and tubular damage. We thus investigated whether canrenoic acid (CA), a mineralocorticoid receptor (MR) antagonist, protects against AKI-induced hepatic and intestinal injury, suggesting the underlying mechanisms. Mice were divided into five groups: sham mice, mice subjected to renal IR, and mice pretreated with canrenoic acid (CA; 1 or 10 mg/kg) 30 min prior to renal IR. At 24 h after renal IR, the levels of plasma creatinine, alanine aminotransferase and aldosterone were measured, and structural changes and inflammatory responses of the kidney, liver, and intestine were analyzed. We found that CA treatment reduced plasma creatinine levels, tubular cell death and oxidative stress induced by renal IR. CA treatment also decreased renal neutrophil infiltration and inflammatory cytokine expression and inhibited the release of high-mobility group box 1 induced by renal IR. Consistently, CA treatment reduced renal IR-induced plasma alanine transaminase, hepatocellular injury and neutrophil infiltration, and inflammatory cytokine expression. CA treatment also decreased small intestinal cell death, neutrophil infiltration and inflammatory cytokine expression induced by renal IR. Taken together, we conclude that MR antagonism by CA treatment protects against multiple organ failure in the liver and intestine after renal IR. [ABSTRACT FROM AUTHOR]

The mineralocorticoid receptor (MR) belongs to the steroid receptor subfamily of nuclear receptors. MR is a transcription factor key in regulating blood pressure and mineral homeostasis. In addition, it plays an important role in a broad range of biological and pathological conditions, greatly expanding its interest as a pharmacological target. Non-steroidal MR antagonists (MRAs) are of particular interest to avoid side effects and achieve tissue-specific modulation of the receptor. The 1,4-dihydropyridine (1,4-DHP) ring has been identified as an appropriate scaffold to develop non-steroidal MRAs. We report the identification of a novel series of 1,4-DHP that has been guided by structure-based drug design, focusing on the less explored DHP position 2. Interestingly, substituents at this position might interfere with MR helix H12 disposition, which is essential for the recruitment of co-regulators. Several of the newly synthesized 1,4-DHPs show interesting properties as MRAs and have a good selectivity profile. These 1,4-DHPs promote MR nuclear translocation with less efficiency than the natural agonist aldosterone, which explains, at least in part, its antagonist character. Molecular dynamic studies are suggestive of several derivatives interfering with the disposition of H12 in the agonist-associated conformation, and thus, they might stabilize an MR conformation unable to recruit co-activators. [ABSTRACT FROM AUTHOR]

Obstructive sleep apnea (OSA) is a chronic and highly prevalent condition that is associated with oxidative stress, inflammation, and fibrosis, leading to endothelial dysfunction, arterial stiffness, and vascular insulin resistance, resulting in increased cardiovascular disease and overall mortality rates. To date, OSA remains vastly underdiagnosed and undertreated, with conventional treatments yielding relatively discouraging results for improving cardiovascular outcomes in OSA patients. As such, a better mechanistic understanding of OSA-associated cardiovascular disease (CVD) and the development of novel adjuvant therapeutic targets are critically needed. It is well-established that inappropriate mineralocorticoid receptor (MR) activation in cardiovascular tissues plays a causal role in a multitude of CVD states. Clinical studies and experimental models of OSA lead to increased secretion of the MR ligand aldosterone and excessive MR activation. Furthermore, MR activation has been associated with worsened OSA prognosis. Despite these documented relationships, there have been no studies exploring the causal involvement of MR signaling in OSA-associated CVD. Further, scarce clinical studies have exclusively assessed the beneficial role of MR antagonists for the treatment of systemic hypertension commonly associated with OSA. Here, we provide a comprehensive overview of overlapping mechanistic pathways recruited in the context of MR activation- and OSA-induced CVD and propose MR-targeted therapy as a potential avenue to abrogate the deleterious cardiovascular consequences of OSA. [ABSTRACT FROM AUTHOR]

The renin–angiotensin–aldosterone system (RAAS) is a major target for treating hypertension and preventing various complications. Mineralocorticoid receptor (MR) antagonists are recommended as specific drugs to ameliorate hyperactive MR signaling, especially for patients with idiopathic hyperaldosteronism. However, the clinical implications of an increased RAAS activity and angiotensin II level induced by MR antagonist administration remain unclear. A 72-year-old Japanese man was referred to our university hospital for refractory hypertension management. He has also had type 2 diabetes mellitus and nephropathy for 8 years. MR antagonists, initiated based on the diagnosis of primary aldosteronism, effectively improved his hypertension. However, proteinuria of 2.5 g/g creatinine, concomitant with an increase in both active renin concentration and plasma aldosterone concentration, occurred. Additional administration of an angiotensin II receptor blocker successfully reduced the plasma aldosterone concentration and proteinuria (<0.3 g/g creatinine). Preserved renal function was confirmed for 1 year thereafter. In conclusion, this case suggests that the angiotensin II receptor is a potential target to treat proteinuria concomitant with primary aldosteronism. RAAS reactivation should be considered when an MR antagonist is initiated for patients with primary aldosteronism, especially idiopathic hyperaldosteronism. [ABSTRACT FROM AUTHOR]

Endometriosis is a chronic inflammatory disease associated with pelvic pain, infertility, and increased cardiovascular risk. Recent studies suggest a possible role of aldosterone as a pro-inflammatory hormone in the pathogenesis of the disease. Cortisol is also an important mediator of stress reaction, but its role is controversial in endometriosis. The aim of this study was to evaluate aldosterone and cortisol levels and blood pressure values in women with endometriosis. We measured blood pressure, plasma aldosterone, renin, cortisol, and dehydroepiandrosterone sulfate (DHEAS) in 20 women with untreated minimal or mild pelvic endometriosis compared with 20 healthy controls matched for age and body mass index. Aldosterone values were similar in the two groups, while renin was significantly lower and the aldosterone to renin ratio was significantly higher in patients with endometriosis than in controls. Systolic blood pressure was in the normal range, but significantly higher in patients with endometriosis. Morning plasma cortisol was normal, but significantly lower in patients with endometriosis compared with controls, while DHEAS to cortisol ratio was similar in the two groups. These preliminary results are evidence of increased biological aldosterone activity and dysregulation of the hypothalamic-pituitary-adrenal axis in early stages of endometriosis. These alterations could play a role in disease development, suggesting new therapeutic targets for aldosterone receptor blockers. [ABSTRACT FROM AUTHOR]

The mineralocorticoid receptor (MR) is a ligand-activated transcription factor that regulates cardiorenal physiology and disease. Ligand-dependent MR transactivation involves a conformational change in the MR and recruitment of coregulatory proteins to form a unique DNA-binding complex at the hormone response element in target gene promoters. Differences in the recruitment of coregulatory proteins can promote tissue-, ligand- or gene-specific transcriptional outputs. The goal of this study was to evaluate the circadian protein TIMELESS as a selective regulator of MR transactivation. TIMELESS has an established role in cell cycle regulation and DNA repair. TIMELESS may not be central to mammalian clock function and does not bind DNA; however, RNA and protein levels oscillate over 24 h. Co-expression of TIMELESS down-regulated MR transactivation of an MR-responsive reporter in HEK293 cells, yet enhanced transactivation mediated by other steroid receptors. TIMELESS markedly inhibited MR transactivation of synthetic and native gene promoters and expression of MR target genes in H9c2 cardiac myoblasts. Immunofluorescence showed aldosterone induces colocalisation of TIMELESS and MR, although a direct interaction was not confirmed by coimmunoprecipitation. Potential regulation of circadian clock targets cryptochrome 1 and 2 by TIMELESS was not detected. However, our data suggest that these effects may involve TIMELESS coactivation of oestrogen receptor alpha (ER). Taken together, these data suggest that TIMELESS may contribute to MR transcriptional outputs via enhancing ERα inhibitory actions on MR transactivation. Given the variable expression of TIMELESS in different cell types, these data offer new opportunities for the development of MR modulators with selective actions. [ABSTRACT FROM AUTHOR]

Aims: The effects of adding a sodium–glucose cotransporter 2 (SGLT2) inhibitor to a mineralocorticoid receptor antagonist (MRA) or an angiotensin receptor–neprilysin inhibitor (ARNI) in patients with heart failure (HF) and mildly reduced ejection fraction (HFmrEF) and preserved ejection fraction (HFpEF) are uncertain, even though the use of all three drugs is recommended in recent guidelines. Methods and results: The efficacy and safety of dapagliflozin added to background MRA or ARNI therapy was examined in patients with HFmrEF/HFpEF enrolled in the DELIVER trial. The primary outcome was the composite of worsening HF or cardiovascular death. Of 6263 patients, 2667 (42.6%) were treated with an MRA and 301 (4.8%) with an ARNI at baseline. Patients taking either were younger, more often men and had lower systolic blood pressure and ejection fraction; they were also more likely to have prior HF hospitalization. The benefit of dapagliflozin was similar whether patients were receiving these therapies. The hazard ratio for the effect of dapagliflozin compared to placebo on the primary outcome was 0.86 (95% confidence interval [CI] 0.74–1.01) for MRA non‐users versus 0.76 (95% CI 0.64–0.91) for MRA users (pinteraction = 0.30). The corresponding values for ARNI non‐users and users were 0.82 (95% CI 0.73–0.92) and 0.74 (95% CI 0.45–1.22), respectively (pinteraction = 0.75). None of the adverse events examined was more common with dapagliflozin compared to placebo overall or in the MRA and ARNI subgroups. Conclusions: The efficacy and safety of dapagliflozin were similar, regardless of background treatment with an MRA or ARNI. SGLT2 inhibitors may be added to other treatments recommended in recent guidelines for HFmrEF/HFpEF. [ABSTRACT FROM AUTHOR]

In diabetic nephropathy, hyperglycemia elevates albumin glycation and also results in increased plasma aldosterone. Both glycation and aldosterone are reported to cause oxidative stress by downregulating the NRF-2 pathway and thereby resulting in reduced levels of antioxidants and glycation detoxifying enzymes. We hypothesize that an interaction between aldosterone and glycated albumin may be responsible for amplified oxidative stress and concomitant renal cell damage. Hence, human serum albumin was glycated by methylglyoxal (MGO) in presence of aldosterone. Different structural modifications of albumin, functional modifications and aldosterone binding were analyzed. HEK-293 T cells were treated with aldosterone+glycated albumin along with inhibitors of receptors for mineralocorticoid (MR) and advanced glycation endproducts (RAGE). Cellular MGO content, antioxidant markers (nitric oxide, glutathione, catalase, superoxide dismutase, glutathione peroxidase), detoxification enzymes (aldose reductase, Glyoxalase I, II), their expression along with NRF-2 and Keap-1 were measured. Aldosterone binds to albumin with high affinity which is static and spontaneous. Cell treatment by aldosterone+glycated albumin increased intracellular MGO, MR and RAGE expression; hampered antioxidant, detoxification enzyme activities and reduced NRF-2, Keap-1 expression. Thus, the glycated albumin-aldosterone interaction and its adverse effect on renal cells were confirmed. The results will help in developing better pharmacotherapeutic strategies for diabetic nephropathy. [ABSTRACT FROM AUTHOR]

The mineralocorticoid receptor (MR) is a member of the steroid receptor family and acts as a ligand-dependent transcription factor. In addition to its classical effects on water and electrolyte balance, its involvement in the pathogenesis of cardiovascular and renal diseases has been the subject of research for several years. The molecular basis of the latter has not been fully elucidated, but an isolated increase in the concentration of the MR ligand aldosterone or MR expression does not suffice to explain long-term pathologic actions of the receptor. Several studies suggest that MR activity and signal transduction are modulated by the surrounding microenvironment, which therefore plays an important role in MR pathophysiological effects. Local changes in micromilieu, including hypoxia, ischemia/reperfusion, inflammation, radical stress, and aberrant salt or glucose concentrations affect MR activation and therefore may influence the probability of unphysiological MR actions. The surrounding micromilieu may modulate genomic MR activity either by causing changes in MR expression or MR activity; for example, by inducing posttranslational modifications of the MR or novel interaction with coregulators, DNA-binding sites, or non-classical pathways. This should be considered when developing treatment options and strategies for prevention of MR-associated diseases. [ABSTRACT FROM AUTHOR]

Aldosterone exerts some of its effects not by binding to mineralocorticoid receptors, but rather by acting via G protein-coupled estrogen receptors (GPER). To determine if aldosterone binds directly to GPER, we studied the ability of aldosterone to compete for the binding of [³H] 2-methoxyestradiol ([³H] 2-ME), a high potency GPER-selective agonist. We used GPER gene transfer to engineer Sf9-cultured insect cells to express GPER. We chose insect cells to avoid interactions with any intrinsic mammalian receptors for aldosterone. [³H] 2-ME binding was saturable and reversible to a high-affinity population of receptors with Kd = 3.7 nM and Bmax = 2.2 pmol/mg. Consistent with agonist binding to G Protein-coupled receptors, [³H] 2-ME high- affinity state binding was reduced in the presence of the hydrolysis-resistant GTP analog, GppNHp. [³H] 2-ME binding was competed for by the GPER agonist G1, the GPER antagonist G15, estradiol (E2), as well as aldosterone (Aldo). The order of potency for competing for [³H] 2-ME binding, namely 2ME > Aldo > E2 ≥ G1, paralleled the orders of potency for inhibition of cell proliferation and inhibition of ERK phosphorylation by ligands acting at GPER. These data confirm the ability of aldosterone to interact with the GPER, consistent with the interpretation that aldosterone likely mediates its GPER-dependent effects by direct binding to the GPER. Significance statement: Despite the growing evidence for aldosterone's actions via G protein-coupled estrogen receptors (GPER), there remains significant skepticism that aldosterone can directly interact with GPER. The current studies are the first to demonstrate directly that aldosterone indeed is capable of binding to the GPER and thus likely mediates its GPER-dependent effects by direct binding to the receptor. [ABSTRACT FROM AUTHOR]

Previous studies indicated a relationship between aldosterone, the mineralocorticoid receptor (MR), and antidepressant treatment outcome. Physiological indicators of MR function (blood pressure and electrolytes) are easily accessible and may therefore serve as useful predictors. Thus, our aim was to investigate the predictive value of peripheral MR-related markers for antidepressant treatment outcomes. 826 MDD patients who had participated in the randomised-controlled Early Medication Change (EMC) trial were analysed. Depression severity and MR-related markers were assessed weekly. In 562 patients, genetic variation of five MR-related genes was determined. Patients with blood pressure <120mmHg showed higher depression severity (p = 0.005) than patients with blood pressure ≥120mmHg. Patients with a melancholic subtype had significantly lower blood pressures (p = 0.004). Na+/K+ ratio was positively and K+-concentration was negatively correlated to depression severity and to relative changes in HAMD from baseline to day 14, and 56 respectively (p < 0.001). For none of the MR-related genes, genetic variation was associated with treatment outcomes. We confirmed early observations of an altered peripheral MR sensitivity, reflected by lower blood pressure, low K+ or high Na+/K+ ratio in patients with more severe depression. These routinely collected biomarkers may potentially be useful for risk stratification in an early stage of treatment. Trial Registration: clinicaltrials.gov Identifier: NCT00974155; [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the effect of acute aldosterone (ALDO) administration on the vascular permeability of skin. ALDO was injected intradermally into rats, and vascular permeability was measured. Eplerenone (EPL), a selective mineralocorticoid receptor (MR) antagonist, was used. Skin biopsies were carried out for immunohistochemical (IHC) staining, and polymerase chain reactions were performed to analyze the expression of MR, 11β-hydroxysteroid dehydrogenase type 2, von Willebrand factor (vWF), vascular endothelial growth factor (VEGF), and zonula occludens 1. Our study showed the presence of MR in the rat skin vasculature for the first time. It was found that ALDO injection resulted in a more than 30% increase in vascular permeability and enhanced the endothelial exocytosis of vWF. The effect of ALDO diminished after EPL administration. An accumulation of vWF and a reduction in VEGF IHC staining were observed following chronic EPL administration. No effect of ALDO or EPL on the mRNA expression of the studied genes or skin structure was observed. The results suggest that ALDO increases vascular permeability in the skin via an MR-dependent mechanism. This effect of ALDO on skin microcirculation may have important therapeutic implications for diseases characterized by increased levels of ALDO and coexisting skin microangiopathy. [ABSTRACT FROM AUTHOR]

Perception of the role of the aldosterone/mineralocorticoid receptor (MR) ensemble has been extended from a previously renal epithelial-centered focus on sodium and volume homeostasis to an understanding of their role as systemic modulators of reactive oxygen species, inflammation, and fibrosis. Steroidal MR antagonists (MRAs) are included in treatment paradigms for resistant hypertension and heart failure with reduced ejection fraction, while more recently, the nonsteroidal MRA finerenone was shown to reduce renal and cardiovascular outcomes in two large phase III trials (FIDELIO-DKD and FIGARO-DKD) in patients with chronic kidney disease and type 2 diabetes, respectively. Here, we provide an overview of the pathophysiologic role of MR overactivation and preclinical evidence with the nonsteroidal MRA finerenone in a range of different disease models with respect to major components of the aggregate mode of action, including interfering with reactive oxygen species generation, inflammation, fibrosis, and hypertrophy. We describe a time-dependent effect of these mechanistic components and the potential modification of major clinical parameters, as well as the impact on clinical renal and cardiovascular outcomes as observed in FIDELIO-DKD and FIGARO-DKD. Finally, we provide an outlook on potential future clinical indications and ongoing clinical studies with finerenone, including a combination study with a sodium–glucose cotransporter-2 inhibitor. [ABSTRACT FROM AUTHOR]

Systemic insulin resistance is characterized by reduced insulin metabolic signaling and glucose intolerance. Mineralocorticoid receptors (MRs), the principal receptors for the hormone aldosterone, play an important role in regulating renal sodium handling and blood pressure. Recent studies suggest that MRs also exist in tissues outside the kidney, including vascular endothelial cells, smooth muscle cells, fibroblasts, perivascular adipose tissue, and immune cells. Risk factors, including excessive salt intake/salt sensitivity, hypertension, and obesity, can lead to the activation of vascular MRs to promote inflammation, oxidative stress, remodeling, and fibrosis, as well as cardiovascular stiffening and microcirculatory impairment. These pathophysiological changes are associated with a diminished ability of insulin to initiate appropriate intracellular signaling events, resulting in a reduced glucose uptake within the microcirculation and related vascular insulin resistance. Therefore, the pharmacological inhibition of MR activation provides a potential therapeutic option for improving vascular function, glucose uptake, and vascular insulin sensitivity. This review highlights recent experimental and clinical data that support the contribution of abnormal MR activation to the development of vascular insulin resistance and dysfunction. [ABSTRACT FROM AUTHOR]

Regulated Na+ transport in the distal nephron is of fundamental importance to fluid and electrolyte homeostasis. Further upstream, Na+ is the principal driver of secondary active transport of numerous organic and inorganic solutes. In the distal nephron, Na+ continues to play a central role in controlling the body levels and concentrations of a more select group of ions, including K+, Ca++, Mg++, Cl−, and HCO3−, as well as water. Also, of paramount importance are transport mechanisms aimed at controlling the total level of Na+ itself in the body, as well as its concentrations in intracellular and extracellular compartments. Over the last several decades, the transporters involved in moving Na+ in the distal nephron, and directly or indirectly coupling its movement to that of other ions have been identified, and their interrelationships brought into focus. Just as importantly, the signaling systems and their components—kinases, ubiquitin ligases, phosphatases, transcription factors, and others—have also been identified and many of their actions elucidated. This review will touch on selected aspects of ion transport regulation, and its impact on fluid and electrolyte homeostasis. A particular focus will be on emerging evidence for site-specific regulation of the epithelial sodium channel (ENaC) and its role in both Na+ and K+ homeostasis. In this context, the critical regulatory roles of aldosterone, the mineralocorticoid receptor (MR), and the kinases SGK1 and mTORC2 will be highlighted. This includes a discussion of the newly established concept that local K+ concentrations are involved in the reciprocal regulation of Na+-Cl− cotransporter (NCC) and ENaC activity to adjust renal K+ secretion to dietary intake. [ABSTRACT FROM AUTHOR]

Objective: The central nucleus of the amygdala (CeA) has dense downward fiber projections towards the nucleus tractus solitary (NTS) and can modulate the activity of NTS taste neurons. However, whether CeA affects the nongenomic role of aldosterone (ALD) in regulating sodium intake at the NTS level remains unclear. Methods: First, 40 adult male Sprague Dawley rats were divided into five groups, referring to different concentrations of ALD, to observe the sodium intake pattern compared with the vehicle (n = 8). ALD, the mineralocorticoid receptor antagonist spironolactone (SPI), and ALD + SPI were injected into the NTS. Then, the rats were divided into four groups (n = 16): bilateral/unilateral CeA electrolytic lesions, bilateral/unilateral CeA sham lesions. After recovery, one stainless steel 23‐gauge cannula with two tubes was implanted into the rat NTS, and all rats underwent a recovery period of 7 days. Then, each group was divided into two subgroups that received aldosterone or control solution injection, and the cumulative intake of 0.3 mol/L NaCl solution was recorded within 30 min. Results: Bilateral CeA lesion eliminated the increased 0.3 mol/L NaCl intake induced by aldosterone microinjected into the NTS (CeA lesion: 0.3 ± 0.04 ml/30 min vs. sham lesion: 1.3 ± 0.3 ml/30 min). Unilateral CeA lesion reduced the increased NaCl intake induced by aldosterone microinjected into the NTS compared with the control group (p <.05) in the first 15 min but not in 15–30 min (p >.05). In sham lesion rats, aldosterone (5 ng/0.1 μl) still induced a significant increase in NaCl intake (aldosterone: 1.3 ± 0.3 ml/30 min vs. control: 0.25 ± 0.02 ml/30 min) (p <.05). Conclusion: The results verified that the complete CeA may play an important role in aldosterone to regulate the nongenomic effect on rapid sodium intake. [ABSTRACT FROM AUTHOR]

The Mineralocorticoid Receptor (MR) mediates the sodium-retaining action of aldosterone in the distal nephron, but mechanisms regulating MR expression are still poorly understood. We previously showed that RNA Binding Proteins (RBPs) regulate MR expression at the post-transcriptional level in response to variations of extracellular tonicity. Herein, we highlight a novel regulatory mechanism involving the recruitment of microRNAs (miRNAs) under hypertonicity. RT-qPCR validated miRNAs candidates identified by high throughput screening approaches and transfection of a luciferase reporter construct together with miRNAs Mimics or Inhibitors demonstrated their functional interaction with target transcripts. Overexpression strategies using Mimics or lentivirus revealed the impact on MR expression and signaling in renal KC3AC1 cells. miR-324-5p and miR-30c-2-3p expression are increased under hypertonicity in KC3AC1 cells. These miRNAs directly affect Nr3c2 (MR) transcript stability, act with Tis11b to destabilize MR transcript but also repress Elavl1 (HuR) transcript, which enhances MR expression and signaling. Overexpression of miR-324-5p and miR-30c-2-3p alter MR expression and signaling in KC3AC1 cells with blunted responses in terms of aldosterone-regulated genes expression. We also confirm that their expression is increased by hypertonicity in vivo in the kidneys of mice treated with furosemide. These findings may have major implications for the pathogenesis of renal dysfunctions, sodium retention, and mineralocorticoid resistance. [ABSTRACT FROM AUTHOR]

PERIOD 1 (PER1) is a circadian clock transcription factor that is regulated by aldosterone, a hormone that increases blood volume and Na+ retention to increase blood pressure. Male global Per1 knockout (KO) mice develop reduced night/day differences in Na+ excretion in response to a high-salt diet plus desoxycorticosterone pivalate treatment (HS þ DOCP), a model of salt-sensitive hypertension. In addition, global Per1 KO mice exhibit higher aldosterone levels on a normal-salt diet. To determine the role of Per1 in the kidney, male kidney-specific Per1 KO (KS-Per1 KO) mice were generated using Ksp-cadherin Cre recombinase to remove exons 2–8 of Per1 in the distal nephron and collecting duct. Male KS-Per1 KO mice have increased Na+ retention but have normal diurnal differences in Na+ excretion in response to HS þ DOCP. The increased Na+ retention is associated with altered expression of glucocorticoid and mineralocorticoid receptors, increased serum aldosterone, and increased medullary endothelin-1 compared with control mice. Adrenal gland gene expression analysis revealed that circadian clock and aldosterone synthesis genes have altered expression in KS-Per1 KO mice compared with control mice. These results emphasize the importance of the circadian clock not only in maintaining rhythms of physiological functions but also for adaptability in response to environmental cues, such as HS þ DOCP, to maintain overall homeostasis. Given the prevalence of salt-sensitive hypertension in the general population, these findings have important implications for our understanding of how circadian clock proteins regulate homeostasis. [ABSTRACT FROM AUTHOR]

The classic focus on the mechanisms of action of aldosterone was directed primarily on its role in modulating renal excretory function and maintaining volume homeostasis. In contrast, many recent studies have demonstrated a much wider and expanded role for aldosterone and for the mineralocorticoid receptor (MR). Activation of the MR promotes inflammation, collagen formation, fibrosis, and necrosis with consequent renal injury. Increasing evidence has accrued that implicates the pathophysiological overactivation of the MR as a major determinant of progression of both diabetic and nondiabetic chronic kidney disease (CKD). By promoting cascades of injury encompassing inflammation and fibrosis, MR overactivation constitutes a pivotal determinant of CKD progression and consequently its associated morbidity and mortality. Based on this mechanism of action, blockade of the MR with the nonsteroidal MR antagonist finerenone is currently being investigated as a novel treatment regimen to slow the progression of CKD. The recently reported FIDELIO-DKD (FInerenone in reducing kiDnEy faiLure and dIsease prOgression in Diabetic Kidney Disease) study demonstrated that patients with CKD and type 2 diabetes (T2D) who were treated with finerenone manifested a lower risk of a composite primary outcome event compared with patients in the placebo arm (defined as kidney failure or a sustained decrease of ≥ 40% in the estimated glomerular filtration rate from baseline, or death from renal causes). In addition, patients in the finerenone group also manifested a lower risk of a key secondary outcome event (defined as death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure). Based on the success of these major clinical trials, finerenone was approved by the FDA on 9 July 2021 as a novel treatment for retarding CKD progression in patients with T2D (https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-drug-reduce-risk-serious-kidney-and-heart-complications-adults-chronic-kidney-disease). 26ETgR3_xjRbcbeEiWzvdM Podcast Video (MP4 258973 KB) [ABSTRACT FROM AUTHOR]

Aim: With diabetes comes a significant risk of macrovascular and microvascular complications. Circulating aldosterone levels increase in patients with diabetes. Aldosterone can directly affect vascular function via activation of the mineralocorticoid receptor (MR). We hypothesized that aldosterone via endothelial MR impairs endothelial function in a murine model of experimental diabetes. Method: Endothelial cell‐specific mineralocorticoid receptor knockout MRflox/flox; Tie2‐Cre mice (ECMR‐KO) and wild‐type FVB littermates were subjected to an experimental type‐1 diabetic model by low dose streptozotocin injections (55mg/kg/day) for five consecutive days. After 10 weeks of diabetes, second‐order mesenteric resistance arteries were perfused ex vivo to evaluate vessel contractility and endothelial function. The effect of ex vivo incubation with aldosterone with and without the antagonist, spironolactone was determined. Results: Diabetic ECMR‐KO and wild‐type mice had similar, elevated, plasma aldosterone concentration while only diabetic wild‐type mice displayed elevated urine albumin excretion and cardiac and kidney hypertrophy at 10 weeks. There were no differences in contraction (Emax and EC50) to thromboxane receptor agonist (U46619) and elevated K+ between groups. Wild‐type diabetic mice showed impaired acetylcholine (ACh)‐dependent relaxation, while diabetic ECMR‐KO mice had intact ACh‐mediated relaxation. Aldosterone incubation ex vivo impaired ACh mediated relaxation and rendered responses similar to diabetic WT arteries. Direct, ex vivo aldosterone effects were absent in ECMR‐KO animals. Ex vivo inhibitory effects of aldosterone on endothelial relaxation in arteries from WT were abolished by spironolactone. Conclusion: These findings show that endothelial cell mineralocorticoid receptor activation accounts for diabetes‐induced systemic endothelial dysfunction in experimental diabetes and may explain the cardiovascular protection by MR antagonists in diabetes. [ABSTRACT FROM AUTHOR]

The nexus of chronic kidney disease (CKD) and cardiovascular disease (CVD) amplifies the morbidity and mortality of CKD, emphasizing the need for defining and establishing therapeutic initiatives to modify and abrogate the progression of CKD and concomitant CV risks. In addition to the traditional CV risk factors, disturbances of mineral metabolism are specific risk factors that contribute to the excessive CV mortality in patients with CKD. These risk factors include dysregulations of circulating factors that modulate phosphate metabolism, including fibroblast growth factor 23 (FGF23) and soluble Klotho. Reduced circulating levels and suppressed renal Klotho expression may be associated with adverse outcomes in CKD patients. While elevated circulating concentrations or locally produced FGF23 in the strained heart exert prohypertrophic mechanisms on the myocardium, Klotho attenuates tissue fibrosis, progression of CKD, cardiomyopathy, endothelial dysfunction, vascular stiffness and vascular calcification. Mineralocorticoid receptor (MR) activation in nonclassical targets, mediated by aldosterone and other ligands, amplifies CVD in CKD. In concert, we detail how the interplay of elevated FGF23, activation of the MR and concomitant reductions of circulating Klotho in CKD may potentiate each other's deleterious effects on the kidney and heart, thereby contributing to the initiation and progression of kidney and cardiac functional deterioration, acting through multipronged, albeit complementary, mechanistic pathways. [ABSTRACT FROM AUTHOR]

Kidney transplantation is associated with increased risk of cardiovascular morbidity. Interleukin (IL)-17A mediates kidney injury. Aldosterone promotes T helper 17 lymphocyte differentiation and IL-17A production through the mineralocorticoid receptor. In this exploratory, post hoc substudy, it was hypothesized that a 1-yr intervention with the mineralocorticoid receptor antagonist spironolactone lowers IL-17A and related cytokines and reduces epithelial injury in kidney transplant recipients. Plasma and urine samples were obtained from kidney transplant recipients from a double-blind randomized clinical trial testing spironolactone (n = 39) versus placebo (n = 41). Plasma concentrations of cytokines interferon-c, IL-17A, tumor necrosis factor-a, IL-6, IL-1b, and IL-10 were determined before and after 1-yr treatment. Urine calbindin-to-creatinine, clusterin-to-creatinine, kidney injury molecule-1-tocreatinine, osteoactivin-to-creatinine, trefoil factor 3 (TFF3)-to-creatinine, and VEGF-to-creatinine ratios were analyzed. Blood pressure and plasma aldosterone concentration at inclusion did not relate to plasma cytokines and injury markers expect for urine TFF3-to-creatinine ratios that correlated positively to blood pressure. None of the cytokines changed in plasma after spironolactone intervention. Plasma IL-17A increased in the placebo-treated group. Spironolactone induced an increase in plasma Kþ (0.4 ± 0.4 mmol/L). This increase did not correlate with plasma IL-17A or urine calbindin and TFF3 changes. Ongoing treatment at inclusion with angiotensin-converting enzyme inhibitor and/or ANG II receptor blockers was not associated with changed levels of IL-17A and injury markers and had no effect on the response to spironolactone. Urinary calbindin and TFF3 decreased in the spironolactone-treated group with no difference in between-group analyses. In conclusion, irrespective of ongoing ANG II inhibition, spironolactone has no effect on plasma IL-17A and related cytokines or urinary injury markers in kidney transplant recipients. [ABSTRACT FROM AUTHOR]

Diabetes-mediated development of micro and macro-vascular complications is a global concern. One of the factors is hyperglycemia induced the non-enzymatic formation of advanced glycation end products (AGEs). Accumulated AGEs bind with receptor of AGEs (RAGE) causing inflammation, oxidative stress and extracellular matrix proteins (ECM) modifications responsible for fibrosis, cell damage and tissue remodeling. Moreover, during hyperglycemia, aldosterone (Aldo) secretion increases, and its interaction with mineralocorticoid receptor (MR) through genomic and non-genomic pathways leads to inflammation and fibrosis. Extensive research on individual involvement of AGEs-RAGE and Aldo-MR pathways in the development of diabetic nephropathy (DN), cardiovascular diseases (CVDs), and impaired immune system has led to the discovery of therapeutic drugs. Despite mutual repercussions, the cross-talk between AGEs-RAGE and Aldo-MR pathways remains unresolved. Hence, this review focuses on the possible interaction of Aldo and glycation in DN and CVDs, considering the clinical significance of mutual molecular targets. • Aldosterone and glycation are involved in the development of diabetic complications. • Aldosterone and glycation cause inflammation, oxidative stress, and fibrosis. • Both pathways share clinically significant molecular targets. • Addressing aldosterone-glycation axis will effectively manage diabetic complications. [ABSTRACT FROM AUTHOR]

• Aldosterone elevated in the colon of DSS-induced colitis mice. • Aldosterone induced the production of IL17A and ROS/RNS in ILC3. • Eplerenone alleviate colitis by inhibiting the pro-inflammation function of ILC3s. • Deletion of Nr3c2 in the ILC3 lineage protected mice from colitis and colitis-associated colorectal cancer. • MR promoted the transcription of IL17A in ILC3. Aldosterone is a key mineralocorticoid involved in regulating the concentration of blood electrolytes and physiological volume balance. Activation of mineralocorticoid receptor (MR) has been recently reported to participate in adaptive and innate immune responses under inflammation. Here, we evaluated the role of aldosterone and MR in inflammation bowel diseases (IBD). Aldosterone elevated in the colon of DSS-induced colitis mice. Aldosterone addition induced IL17 production and ROS/RNS level in group 3 innate lymphoid cells (ILC3s) and exacerbated intestinal injury. A selective mineralocorticoid receptor antagonism, eplerenone, inhibited IL17-producing ILC3s and its ROS/RNS production, protected mice from DSS-induced colitis. Mice lacking Nr3c2 (MR coding gene) in ILC3s exhibited decreased IL17 and ROS/RNS production, which alleviated colitis and colitis-associated colorectal cancer (CAC). Further experiments revealed that MR could directly bind to IL17A promoter and facilitate its transcription, which could be enhanced by aldosterone. Thus, our findings demonstrated the critical role of aldosterone-MR-IL17 signaling in ILC3s and gut homeostasis, indicating the therapeutic strategy of eplerenone in IBD clinical trial. [ABSTRACT FROM AUTHOR]

Inconsistencies have been reported on the effect of sex on aldos terone (ALDO) levels leading to clinical confusion. The reasons for these inconsistencies are uncertain but include estrogen and/or its receptor modulating target gene responses to mineralocorticoid receptor activation and ALDO secretagogues' levels. This study's goal was to determine whether ALDO's biosynthesis also differed by se x. Two approaches were used. First, plasma renin activity and aldosterone were measured in rats. Both were significantly higher in males. Secondly, using rat zona glo merulosa (ZG) cells, we assessed three ex vivo areas: (1) activity/levels of early steps in ALDO's biosynthesis (StAR and CYP11A1); (2) activity/levels of a late step (CYP11B2); and (3) the status of the mineralocorticoid receptor (MR)-mediated, ultrashort feedback loop. Females had higher expression of CYP11A1 and StAR and increased CYP11A1 activity (increased pregnenolone/corticosterone levels) but did not differ in CYP11B 2 expression or activity (ALDO levels). Activating the ZG's MR (thereby activating the u ltrashort feedback loop) reduced CYP11B2's activity similarly in both sexes. Ex vivo, these molecular effects were accompanied, in females, by lower ALDO basally but higher ALDO with angiotensin II stimulation. In conclusion, we documented that not only was there a sex-mediated difference in the activity of ALDO's biosynthesis but also these differences at the molecular level help explain the variable reports on ALDO's circulating levels. Basally, both in vivo and ex vivo, males had higher ALDO levels, likely secondary to higher ALDO secretagogue levels. However, in response to acute stimulation, ALDO levels are higher in females because of the greater levels and/or activity of their StAR/CYP11A1. [ABSTRACT FROM AUTHOR]

Aldosterone is produced from the zona glomerulosa of the adrenal cortex in the adrenal gland, which is main mineralocorticoid hormone. Upon binding the mineralocorticoid receptor, it regulates sodium and potassium absorption, secretion, and retention, thereby maintaining stable blood pressure levels. However, abnormal aldosterone synthesis and metabolism could be pathogenic and contribute to multiple organ fibrosis and structural remodeling. For instance, hyperaldosteronemia is critically involved in the development of hypertension, heart failure (HF), and renal disease. Therefore, mineralocorticoid receptor antagonists (MRAs) that could fight against high concentrations of aldosterone play an important role in the treatment of diseases caused by hyperaldosteronism. Eplerenone, as a novel selective MRA, has better therapeutic efficiency and fewer side effects comparing to the classical drug spironolactone. In this review, first, we go through the biosynthesis and biologic properties of aldosterone and then introduce how hyperaldosteronemia facilitates certain diseases progression. Aldosterone is an important part of the renin-angiotensin-aldosterone system (RAAS), which plays a crucial role in essential hypertension, atrial tremor, and tissue fibrosis. Second, we summarize current evidence of clinical application of eplerenone in the control of primary aldosteronism, hypertension, HF, nephropathy, insulin resistance, and liver damage. It is exciting that many studies have shown that the use of eplerenone in these diseases yields good outcomes accompanied with fewer adverse effects such as hyperkalemia, metabolic acidosis, hypotension, and acute kidney failure, which indicates that eplerenone is a strong and safe MRA and inhibitor of RAAS system. This review focuses on therapeutic efficacy and disadvantages of eplerenone when treating a series of different diseases. Ultimately, we hope to shed light on future therapeutic strategies in diseases associated with hyperaldosteronemia. [ABSTRACT FROM AUTHOR]

Cardiovascular (CV) stiffening represents a complex series of events evolving from pathological changes in individual cells of the vasculature and heart which leads to overt tissue fibrosis. While vascular stiffening occurs naturally with ageing it is accelerated in states of insulin (INS) resistance, such as obesity and type 2 diabetes. CV stiffening is clinically manifested as increased arterial pulse wave velocity and myocardial fibrosis-induced diastolic dysfunction. A key question that remains is how are these events mechanistically linked. In this regard, heightened activation of vascular mineralocorticoid receptors (MR) and hyperinsulinaemia occur in obesity and INS resistance states. Further, a downstream mediator of MR and INS receptor activation, the endothelial cell Na+ channel (EnNaC), has recently been identified as a key molecular determinant of endothelial dysfunction and CV fibrosis and stiffening. Increased activity of the EnNaC results in a number of negative consequences including stiffening of the cortical actin cytoskeleton in endothelial cells, impaired endothelial NO release, increased oxidative stress-meditated NO destruction, increased vascular permeability, and stimulation of an inflammatory environment. Such endothelial alterations impact vascular function and stiffening through regulation of vascular tone and stimulation of tissue remodelling including fibrosis. In the case of the heart, obesity and INS resistance are associated with coronary vascular endothelial stiffening and associated reductions in bioavailable NO leading to heart failure with preserved systolic function (HFpEF). After a brief discussion on mechanisms leading to vascular stiffness per se , this review then focuses on recent findings regarding the role of INS and aldosterone to enhance EnNaC activity and associated CV stiffness in obesity/INS resistance states. Finally, we discuss how coronary artery-mediated EnNaC activation may lead to cardiac fibrosis and HFpEF, a condition that is especially pronounced in obese and diabetic females. [ABSTRACT FROM AUTHOR]

Vascular calcification is common in chronic kidney disease (CKD) and associated with increased cardiovascular mortality. Aldosterone has been implicated as an augmenting factor in the progression of vascular calcification. The present study further explored putative beneficial effects of aldosterone inhibition by the mineralocorticoid receptor antagonist spironolactone on vascular calcification in CKD. Serum calcification propensity was determined in serum samples from the MiREnDa trial, a prospective, randomized controlled clinical trial to investigate efficacy and safety of spironolactone in maintenance hemodialysis patients. Experiments were conducted in mice with subtotal nephrectomy and cholecalciferol treatment, and in calcifying primary human aortic smooth muscle cells (HAoSMCs). Serum calcification propensity was improved by spironolactone treatment in patients on hemodialysis from the MiREnDa trial. In mouse models and HAoSMCs, spironolactone treatment ameliorated vascular calcification and expression of osteogenic markers. These observations support a putative benefit of spironolactone treatment in CKD-associated vascular calcification. Further research is required to investigate possible improvements in cardiovascular outcomes by spironolactone and whether the benefits outweigh the risks in patients with CKD. • Spironolactone improves calcification propensity (T 50) in hemodialysis patients. • Spironolactone ameliorates vascular calcification in subtotal nephrectomized mice. • Spironolactone reduces cholecalciferol-induced vascular calcification in mice. • Spironolactone blunts high calcium-induced VSMC calcification. [ABSTRACT FROM AUTHOR]

The therapeutic options for preventing or slowing the progression of chronic kidney disease (CKD) have been thus far limited. While angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs) are, without a doubt, safe and effective drugs, a significant proportion of patients with CKD still progress to end‐stage kidney disease. After decades of negative trials, nephrologists have finally found cause for optimism with the introduction of sodium‐glucose cotransporter‐2 (SGLT2) inhibitors and non‐steroidal mineralocorticoid receptor antagonists (MRAs). Recent trials such as EMPA‐REG OUTCOME and CREDENCE have provided evidence of the renal benefits of SGLT2 inhibitors, which have now found widespread acceptance as first‐line agents for diabetic CKD, in addition to ACEi/ARBs. Considering results from the DAPA‐CKD study, it is expected that their use will soon be expanded to other causes of albuminuric CKD as well, although confirmation from further trials, such as the EMPA‐KIDNEY study is awaited. Likewise, although the role of mineralocorticoid receptor overactivation in CKD progression has been known for decades, it is only now with the FIDELIO‐DKD study that we have evidence of benefits of MRAs on hard renal endpoints, specifically in patients with diabetic CKD. While further research is ongoing, given the evidence of synergism between the three drug classes, it is foreseeable that a combination of two or more of these drugs may soon become the standard of care for CKD, regardless of underlying aetiology. This review describes pathophysiologic mechanisms, current evidence and future perspectives on the use of SGLT2 inhibitors and novel MRAs in CKD. SUMMARY AT A GLANCE: This is a comprehensive review of two important agents that have emerged in recent years, namely the SGLT‐2 inhibitor and the non‐steroidal MRA, in the management of diabetic kidney disease. [ABSTRACT FROM AUTHOR]

Fine tuning of Na+ reabsorption takes place along the aldosterone-sensitive distal nephron, which includes the collecting duct (CD), where it is mainly regulated by aldosterone. In the CD, Na+ reabsorption is mediated by the epithelial Na+ channel and Na+ pump (Na+-K+-ATPase). Paracellular ion permeability is mainly dependent on tight junction permeability. Claudin-8 is one of the main tight junction proteins expressed along the aldosterone-sensitive distal nephron. We have previously shown a coupling between transcellular Na+ reabsorption and paracellular Na+ barrier. We hypothesized that aldosterone controls the expression levels of both transcellular Na+ transporters and paracellular claudin-8 in a coordinated manner. Here, we show that aldosterone increased mRNA and protein levels as well as lateral membrane localization of claudin-8 in cultured CD principal cells. The increase in claudin-8 mRNA levels in response to aldosterone was prevented by preincubation with 17-hydroxyprogesterone, a mineralocorticoid receptor antagonist, and by inhibition of transcription with actinomycin D. We also showed that a low-salt diet, which stimulated aldosterone secretion, was associated with increased claudin-8 abundance in the mouse kidney. Reciprocally, mice subjected to a high-salt diet, which inhibits aldosterone secretion, or treated with spironolactone, a mineralocorticoid receptor antagonist, displayed decreased claudin-8 expression. Inhibition of glycogen synthase kinase-3, Lyn, and Abl signaling pathways prevented the effect of aldosterone on claudin-8 mRNA and protein abundance, suggesting that signaling of protein kinases plays a permissive role on the transcriptional activity of the mineralocorticoid receptor. This study shows that signaling via multiple protein kinases working in concert mediates aldosterone-induced claudin-8 expression in the CD. [ABSTRACT FROM AUTHOR]

The epithelial Na+ channel (ENaC) constitutes the rate-limiting step for Na+ absorption in the aldosterone-sensitive distal nephron (ASDN) comprising the late distal convoluted tubule (DCT2), connecting tubule (CNT), and collecting duct (CD). Previously, we demonstrated that ENaC activity in the DCT2/CNT transition zone is constitutively high and independent of aldosterone, in contrast to its aldosterone dependence in the late CNT/initial cortical CD (CCD). The mineralocorticoid receptor (MR) is expressed in the entire ASDN. Its activation by glucocorticoids is prevented through 11b-hydroxysteroid dehydrogenase 2 (11b-HSD2) abundantly expressed in the late but probably not early part of the ASDN. We hypothesized that ENaC function in the early part of the ASDN is aldosterone independent but may depend on MR activated by glucocorticoids due to low 11b-HSD2 abundance. To test this hypothesis, we used doxycycline-inducible nephron-specific MR-deficient [MR knockout (KO)] mice. Whole cell ENaC currents were investigated in isolated nephron fragments from the DCT2/CNT or CNT/CCD transition zones using the patch-clamp technique. ENaC activity was detectable in the CNT/CCD of control mice but absent or barely detectable in the majority of CNT/CCD preparations from MR KO mice. Importantly, ENaC currents in the DCT2/CNT were greatly reduced in MR KO mice compared with ENaC currents in the DCT2/CNT of control mice. Immunofluorescence for 11b-HSD2 was abundant in the CCD, less prominent in the CNT, and very low in the DCT2. We conclude that MR is critically important for maintaining aldosterone-independent ENaC activity in the DCT2/CNT. Aldosterone-independent MR activation is probably mediated by glucocorticoids due to low expression of 11b-HSD2. [ABSTRACT FROM AUTHOR]

Background: Renin–angiotensin–aldosterone system (RAAS) blockade with angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB) is the cornerstone of antihypertensive treatment in patients with chronic kidney disease (CKD) and diabetes mellitus. Mineralocorticoid receptor antagonists (MRA) on top of conventional RAAS blockade confer cardio- and renoprotective effects. Yet, the detailed effects of this therapeutic approach on key RAAS effectors have not been elucidated to date. Methods: In this exploratory placebo-controlled study, 15 patients with CKD stages 2–3 and albuminuria due to diabetic kidney disease (DKD) were randomized to receive the MRA eplerenone or placebo in addition to ACEi therapy. Employing mass-spectrometry, we quantified plasma angiotensin levels [Ang I, Ang II, Ang-(1–7), Ang-(1–5), Ang III, Ang IV], renin and aldosterone in patients before and after 8 weeks of MRA treatment. Results: While blood pressure and kidney function were similar in the placebo and eplerenone treatment group during the study period, distinct differences in RAAS regulation occurred: eplerenone treatment resulted in an increase in plasma renin activity, Ang I and aldosterone concentrations, indicating global RAAS activation. In addition, eplerenone on top of ACEi profoundly upregulated the alternative RAAS effector Ang-(1–7). Conclusions: Combined eplerenone and ACEi therapy increases Ang-(1–7) levels in patients with CKD indicating a unique nephroprotective RAAS pattern with considerable therapeutic implications. [ABSTRACT FROM AUTHOR]

Background: Despite clinical evidence indicating poor muscle health in subjects with primary aldosteronism (PA), it is still unclear whether the role of aldosterone in muscle metabolism is direct or mediated indirectly via factors, such as electrolyte imbalance or impaired glucose uptake. As one approach to clarify this issue, we investigated the effect of aldosterone on in vitro myogenesis and the potential mechanism explaining it. Methods: Myogenesis was induced in mouse C2C12 myoblasts with 2% horse serum. Immunofluorescence, quantitative reversetranscription polymerase chain reaction, Western blot, viability, and migration analyses were performed for experimental research. Results: Recombinant aldosterone treatment suppressed muscle differentiation from mouse C2C12 myoblasts in a dose-dependent manner, and consistently reduced the expression of myogenic differentiation markers. Furthermore, aldosterone significantly increased intracellular reactive oxygen species (ROS) levels in myotubes, and treatment with N-acetyl cysteine, a potent biological thiol antioxidant, reversed the decrease of myotube area, myotube area per myotube, nucleus number per myotube, and fusion index due to aldosterone through decreasing oxidative stress. A binding enzyme-linked immunosorbent assay confirmed that mineralocorticoid receptor (MR) interacted with aldosterone in C2C12 myoblasts, while eplerenone, an MR inhibitor, blocked aldosterone-stimulated intracellular ROS generation during myogenesis and markedly attenuated the suppression of in vitro myogenesis by aldosterone. Conclusion: These findings support the hypothesis that hypersecretion of aldosterone, like PA, directly contributes to muscular deterioration and suggest that antioxidants and/or MR antagonists could be effective therapeutic options to reduce the risk of sarcopenia in these patients. [ABSTRACT FROM AUTHOR]

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 (<5 years; male/female, Caucasians) and 10 healthy control participants (male/female, Caucasians). On 2 experimental days, before and at the end of the 8 weeks of treatment with mineralocorticoid blockade, a two‐stage hyperinsulinemic‐isoglycemic clamp (20 and 50 mU∙m−2min−1) was performed for the determination of insulin sensitivity. No change in insulin sensitivity was detected at the end of the mineralocorticoid blockade in the individuals with type 2 diabetes or the healthy controls. Both before and at the end of the treatment with mineralocorticoid blockade, the individuals with type 2 diabetes had a lower insulin sensitivity compared to healthy controls. In conclusion, mineralocorticoid receptor blockade does not appear to improve insulin sensitivity in individuals with type 2 diabetes. Clinical Trial Registration: NCT03017703. https://clinicaltrials.gov/ct2/show/NCT03017703 [ABSTRACT FROM AUTHOR]

Rhesus C glycoprotein (Rhcg), an ammonia transporter, is a key molecule in urinary acid excretion and is expressed mainly in the intercalated cells (ICs) of the renal collecting duct. In the present study we investigated the role of aldosterone in the regulation of Rhcg expression. In in vivo experiments using C57BL/6J mice, Western blot analysis showed that continuous subcutaneous administration of aldosterone increased the expression of Rhcg in membrane fraction of the kidney. Supplementation of potassium inhibited the effect of aldosterone on the Rhcg. Next, mice were subjected to adrenalectomy with or without administration of aldosterone, and then ad libitum 0.14 M NH4Cl containing water was given. NH4Cl load increased the expression of Rhcg in membrane fraction. Adrenalectomy decreased NH4Cl-induced Rhcg expression, which was restored by administration of aldosterone. Immunohistochemical studies revealed that NH4Cl load induced the localization of Rhcg at the apical membrane of ICs in the outer medullary collecting duct. Adrenalectomy decreased NH4Cl-induced membrane localization of Rhcg, which was restored by administration of aldosterone. For in vitro experiments, IN-IC cells, an immortalized cell line stably expressing Flag-tagged Rhcg (Rhcg-Flag), were used. Western blot analysis showed that aldosterone increased the expression of Rhcg-Flag in membrane fraction, while the increase in extracellular potassium level inhibited the effect of aldosterone. Both spiron olactone and GÓ§6983, a PKC inhibitor, inhibited the expression of Rhcg-Flag in the membrane fraction. These results suggest that aldosterone regulates the membrane expression of Rhcg through the mineralocorticoid receptor and PKC pathways, which is modulated by extracellular potassium level. [ABSTRACT FROM AUTHOR]

We used a dataset from a Japanese nationwide registry of patients with primary aldosteronism, to determine which of the parameters of hyperaldosteronism and blood pressure before or after treatments for primary aldosteronism (i.e., surgical adrenalectomy or a medication treatment) are important in terms of cardiovascular prognosis. We assessed whether plasma aldosterone-to-renin ratio and pulse pressure levels before treatment and 6 months after treatment were associated with composite cardiovascular disease events during the 5-year follow-up period. The cohort included 1987 patients (mean age was 53.2 years, 52.0% were female, 37.2% had undergone surgical treatment, and the remainder had been treated with mineralocorticoid receptor antagonists). In the Cox proportional hazard model, the covariate-adjusted hazard ratio (95% confidence interval) for the composite cardiovascular disease events risk for each one-standard-deviation increase in the aldosterone-to-renin ratio or pulse pressure before treatment, those after treatment, or the duration of hypertension were 1.24 (1.05, 1.48), 0.74 (0.54, 1.02), and 1.07 (0.79, 1.44), 1.43 (1.07, 1.92), and 1.52 (1.19, 1.95), respectively. Patients with a high pre-treatment aldosterone-to-renin ratio of more than 603 and a large post-treatment pulse pressure of more than 49 mmHg showed approximately three-fold higher hazard ratios for cardiovascular events risk compared to those with a lower aldosterone-to-renin ratio and smaller pulse pressure. Higher aldosterone-to-renin ratio before treatments, higher pulse pressure after treatments, and longer duration of hypertension were prognostic factors for cardiovascular diseases. Early intervention may be important for preventing cardiovascular disease among patients with primary aldosteronism. [Display omitted] • Higher pulse pressure after treatments for primary aldosteronism (PA) was a risk factor for cardiovascular diseases (CVD). • Our results suggest that the risk of CVD is associated with how arteriosclerosis progresses before initiating treatment. • Early intervention may be important for preventing CVD among patients with PA. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Aldosterone plays a key role in controlling blood pressure (BP) values by maintaining body salt, water, and fluid homeostasis. Excess aldosterone production is associated with arterial hypertension, cardiovascular and metabolic diseases, partly via generation of an inflammatory state followed by fibrotic changes in the organs that are target of hypertension. Aldosterone exerts genomic effects that are known to involve activation of the mineralocorticoid receptor (MR). Other aldosterone effects, including those usually defined as 'rapid' or 'non genomic', involve additional receptors as the G-protein coupled estrogen receptor (GPER). To date, the receptor(s) implicated in the inflammatory action of aldosterone in cells of the innate and adaptive immunity are unknown. Considering the potential role of T-lymphocytes in adaptive immunity in arterial hypertension and related hypertension-mediated organ damage (HMOD), we herein investigated and quantified the expression of the MR and GPER in human CD4+ and CD8+ T-cells. Results provided compelling evidence for the presence at the mRNA and protein level and suggest a functional role of these receptors in the two T -lymphocyte subtypes, thus indicating that they can represent a potential target for modulation of steroid hormone-induced inflammation and ensuing HMOD. [ABSTRACT FROM AUTHOR]