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The glucocorticoid and mineralocorticoid receptors (GR and MR, respectively) have distinct, yet overlapping physiological and pathophysiological functions. There are indications that both receptors interact functionally and physically, but the precise role of this interdependence is poorly understood. Here, we analyzed the impact of GR coexpression on MR genome-wide transcriptional responses and chromatin binding upon activation by aldosterone and glucocorticoids, both physiological ligands of this receptor. Transcriptional responses of MR in the absence of GR result in fewer regulated genes. In contrast, coexpression of GR potentiates MR-mediated transcription, particularly in response to aldosterone, both in cell lines and in the more physiologically relevant model of mouse colon organoids. MR chromatin binding is altered by GR coexpression in a locus- and ligand-specific way. Single-molecule tracking of MR suggests that the presence of GR contributes to productive binding of MR/aldosterone complexes to chromatin. Together, our data indicate that coexpression of GR potentiates aldosterone-mediated MR transcriptional activity, even in the absence of glucocorticoids., Competing Interests: Competing interests statement:The authors declare no competing interest.

Osteonecrosis of the femoral head (ONFH) is a common complication of glucocorticoid (GC) therapy. Recent advances demonstrate that sympathetic nerves regulate bone homeostasis, and GCs lower the sympathetic tone. Here, we show that the dramatically decreased sympathetic tone is closely associated with the pathogenesis of GC-induced ONFH. GCs activate the glucocorticoid receptor (GR) but hinder the activation of the mineralocorticoid receptor (MR) on neurons in the hypothalamic paraventricular nucleus (PVN). This disrupts the balance of corticosteroid receptors (GR/MR) and subsequently reduces the sympathetic outflow in the PVN. Vascular endothelial cells rapidly react to inhibition of sympathetic tone by provoking endothelial apoptosis in adult male mice treated with methylprednisolone (MPS) daily for 3 days, and we find substantially reduced H-type vessels in the femoral heads of MPS-treated ONFH mice. Importantly, treatment with a GR inhibitor (RU486) in the PVN promotes the activation of MR and rebalances the ratio of GR and MR, thus effectively boosting sympathetic outflow, as shown by an increase in tyrosine hydroxylase expression in both the PVN and the sympathetic postganglionic neurons and an increase in norepinephrine levels in both the serum and bone marrow of the femoral head of MPS-treated mice. Rebalancing the corticosteroid receptors mitigates GC-induced endothelial impairment and ONFH and promotes angiogenesis coupled with osteogenesis in the femoral head, while these effects are abolished by chemical sympathectomy with 6-OHDA or adrenergic receptor-β2 (Adrb2) knockout. Furthermore, activating Adrb2 signaling in vivo is sufficient to rescue the GC-induced ONFH phenotype. Mechanistically, norepinephrine increases the expression of the key glycolytic gene 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) via Adrb2-cyclic AMP response element-binding protein (CREB) signaling. Endothelial-specific overexpression of PFKFB3 attenuates endothelial impairment and prevents severe osteonecrosis in MPS-treated Adrb2 knockout mice. Thus, GC inhibits sympathetic tone via the hypothalamic descending pathway, which, in turn, acts as a mediator of GC-induced ONFH., (© 2024. The Author(s).)

Mineralocorticoid receptors are expressed in several structures of the central nervous system, and aldosterone levels can be measured in the brain, although in smaller amounts than in plasma. Nevertheless, these amounts appear to be sufficient to elicit substantial clinical effects. Primary aldosteronism, characterized by high levels of plasma aldosterone, is one of the most common causes of secondary hypertension. In this context, high aldosterone levels may have both indirect and direct effects on the brain with a negative impact on several cerebral functions. Thus, chronic aldosterone excess has been associated with symptoms of anxiety and depression - two clinical entities themselves associated with cognitive deficits. Today, there is an increasing number of reports on the influence of aldosterone on the brain, but there is also a significant amount of uncertainty, such as the role of high aldosterone levels on cognitive functions and decline independently of blood pressure. In this mini review, we discuss the known and unknowns of the impact of aldosterone on the brain putting emphasis on cognitive functions., Competing Interests: Grants or contracts made to the institution: BG, KN National Science Centre, Poland; Consulting fees for the author and his institution: KN Idorsia; Honoraria for lectures: KN Adamed, Bausch, Berlin-Chemie/Menarini, Egis, Idorsia, Gedeon Richter, Gilead, Janssen, Krka, Novo Nordisk, Polpharma, Recordati, Sandoz, Servier; Advisory Board: KN Idorsia; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: MB Servier, Menarini, Bayer, Boehringer. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Nieckarz, Graff, Burnier, Marcinkowska and Narkiewicz.)

Endothelial dysfunction exacerbates hypertension and other vascular complications in diabetes mellitus (DM). Circulating microparticles (MPs) and extracellular vesicles released in patients with DM have emerged as novel regulators of endothelial dysfunction. The obstruction of mineralocorticoid receptors (MRs) is a potential therapeutic approach to reduce cardiovascular complications. Their impact on the obstruction of MRs on circulating MPs and endothelial dysfunction in DM remains unclear. DM was induced in mice through a single intravenous dose of streptozotocin (STZ; 200 mg/kg). Esaxerenone (ESAX; 3 mg/kg/day), a MR blocker was administered via diet for 8 weeks. In this study, the aortas of the DM group showed the endothelial dysfunction and the administration of ESAX ameliorated the endothelial-dependent responses. Moreover, ESAX influences the impaired endothelial-dependent responses of DM-derived MPs. Interestingly, MP levels increased in DM whereas decreased after ESAX administration. In the aorta, the DM-derived MPs increased the expression of intercellular adhesion molecule-1 (ICAM-1). ESAX inhibited the adhesion of DM-derived MPs. Moreover, the ICAM-1 inhibitor A205804 shows similar effects as ESAX. These results indicate that the release and adhesion properties of MPs can be partially obstructed by ESAX via the ICAM-1 signaling pathway, which clarifies the other functions beyond the anti-hypertensive effects of ESAX., (© 2024. The Author(s).)

Although early studies were able to demonstrate a negative impact of stress on working memory performance, present research findings are heterogeneous. Numerous further studies found no effects or even improved performance, with the direction of these stress effects likely depending on the underlying biological mechanisms. The aim of this study was to investigate receptor-specific effects, as part of the stress-induced cortisol response, on working memory performance. Healthy, male participants (N=318, mean age 25.4 ± 5.1y) were exposed to the Trier Social Stress Test (TSST), a social-evaluative stress manipulation, or a non-stress control condition after they had received either spironolactone (blockade of the mineralocorticoid receptor, MR) or mifepristone (blockade of the glucocorticoid receptor, GR) or a placebo. Both substances are potent antagonists with high affinity for the respective receptors. To assess working memory, we implemented the n-back task subsequent to stress exposure, number of correct responses and reaction times served as outcome measures. We did not find effects of stress on working memory for any outcome measure, i.e. correct responses and reaction times. Yet, post hoc tests revealed that the group that received mifepristone exhibited longer reaction times under medium load conditions when compared to the placebo group, which might be an indication of the GR's involvement in task performance. We conclude that working memory performance is not affected by acute stress, at least under these prevalent conditions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. Morag J Young reports financial support was provided by Baker Trustees and Baker HDI. Viet Q.Ho reports a relationship with Monash University that includes: funding grants. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Mood disorders mainly affect the patient's daily life, lead to suffering and disability, increase the incidence rate of many medical illnesses, and even cause a trend of suicide. The glucocorticoid (GC)-mediated hypothalamus-pituitary-adrenal (HPA) negative feedback regulation plays a key role in neuropsychiatric disorders. The balance of the mineralocorticoid receptor (MR)/glucocorticoid receptor (GR) level contributes to maintaining the homeostasis of the neuroendocrine system. Consistently, a chronic excess of GC can also lead to HPA axis dysfunction, triggering anxiety, depression, memory loss, and cognitive impairment. The animal model induced by chronic corticosterone (CORT) administration has been widely adopted because of its simple replication and strong stability. This review summarizes the behavioral changes and underlying mechanisms of chronic CORT administration-induced animal models, including neuroinflammatory response, pyroptosis, oxidative stress, neuroplasticity, and apoptosis. Notably, CORT administration at different doses and cycles can destroy the balance of the MR/GR ratio to make dose-dependent effects of CORT on the central nervous system (CNS). This work aims to offer an overview of the topic and recommendations for future cognitive function research.

The mineralocorticoid system, comprising the renin-angiotensin-aldosterone system (RAAS) and associated receptors, is traditionally viewed as a regulator of sodium and fluid balance and blood pressure (BP), with the main mineralocorticoid hormone aldosterone acting via the mineralocorticoid receptor (MR) in distal renal tubules. Over the past few decades, there has been a wider understanding of the role of the mineralocorticoid system in regulating both classical BP-dependent and non-BP-dependent systemic effects. Mounting evidence indicates the novel role of the mineralocorticoid system in cardiometabolic health, with excess mineralocorticoid system activity being associated with adiposity, diabetes, insulin resistance and cardiovascular diseases independent of its effect on BP, and RAAS blockade and MR antagonists offering protection against cardiometabolic dysfunction. The metabolic manifestations of mineralocorticoid system overactivation are mainly mediated by their interactions with adipose tissue, which orchestrates energy, lipids, and glucose homeostasis via effects on the functions of brown and white adipocytes and immune cells. Adipose tissue can, in turn, influence mineralocorticoid system activity by harboring its own RAAS system and by releasing mineralocorticoid-secretory factors/adipokines, resulting in further progression of cardiometabolic dysfunction. This article discusses the interplay between the mineralocorticoid system and adipose tissue in the pathophysiology of cardiometabolic diseases.

Steroidal mineralocorticoid receptor antagonists (MRAs) bind to the mineralocorticoid receptor and antagonize the effects of aldosterone, which contributes to the development and progression of cardio- and renovascular diseases. Guidelines recommend steroidal MRAs in patients with heart failure with reduced or mildly reduced ejection fraction, as they reduce morbidity and mortality. In heart failure with preserved ejection fraction, MRAs have not convincingly shown to improve prognosis. Steroidal MRAs delay the progression of chronic kidney disease, reduce proteinuria and lower blood pressure in resistant hypertension but can induce hyperkalaemia. Due to their limited selectivity to the mineralocorticoid receptor, steroidal MRAs can cause significant adverse effects, i.e. libido loss, erectile dysfunction, gynaecomastia, and amenorrhoea, leading to low rates of persistance. Against this background, new avenues for developing non-steroidal, selective (ns)MRAs and aldosterone-synthase inhibitors have been taken. Finerenone has been shown to delay the progression of diabetic nephropathy and lower the incidence of heart failure hospitalizations in patients with chronic kidney disease and diabetes compared with placebo. Finerenone has therefore been recommended by the 2023 European Society of Cardiology Guidelines for the management of diabetes in patients with type 2 diabetes and chronic kidney disease. Further randomized controlled trials assessing the safety and effectiveness of finerenone in patients with heart failure are currently ongoing. Esaxerenone provides antihypertensive effects and has been approved for the treatment of hypertension in Japan. Baxdrostat and lorundostat, novel selective aldosterone-synthase inhibitors, are currently under investigation. In phase II trials, baxdrostat and lorundostat were safe and effective in lowering blood pressure in resistant hypertension. In this review, we summarize and critically discuss the evidence for new drugs mitigating aldosterone in heart failure, hypertension, and chronic kidney disease., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Purpose: Overactivation of the mineralocorticoid receptor (MR) pathway is proinflammatory and contributes to the pathogenesis of diabetic retinopathy and of age-related macular degeneration. Excess of aldosterone, the specific MR ligand, is known to stimulate the production of proinflammatory cytokines and chemokines in extrarenal tissues and cells. In the RPE/choroid complex, aldosterone upregulated genes encoding proteins of the inflammatory response and downregulated genes encoding proteins involved in synaptic activity and neurotransmitters. Yet, cortisol, which is the main MR ligand in the eye, is a potent anti-inflammatory endogenous glucocorticoid. The aim of the present work was to better understand the role of MR activation in retinal inflammation either by acute injection of aldosterone or overexpression of the receptor., Methods: We first analyzed the retinal transcriptomic regulation induced by acute intraocular injection of aldosterone in the rat. Then, we used a transgenic rat overexpressing human MR (hMR) to also conduct retinal transcriptomic analysis as well as histological evaluation of the retina, retinal pigment epithelium and choroid., Results: Our results show that acute intravitreal injection of aldosterone is highly proinflammatory, upregulating pathways related to microglial activation, oxidative stress, cell death, and downregulating pathways related to glial/neuronal cells activity and proper neurotransmission. On the other hand, hMR overexpression mediates a low-grade inflammation in the retina, associated with notable choroidal inflammation and choroidal neuropathy., Conclusions: Consequences of hMR overexpression or aldosterone-injection on retinal transcriptome reveal very distinct pathological mechanisms, with only a few common genes regulated, most of them not being regulated in the same way. Although aldosterone is highly proinflammatory in the retina, MR overactivation in its physiologic milieu mediates a low-grade inflammation in the neural retina.

Objective: Here, we aimed to investigate the role of glucocorticoid and mineralocorticoid receptors (GRs and MRs, respectively) in the regulation of energy homeostasis., Methods: We used three mouse models with simultaneous deletion of GRs and MRs in either forebrain neurons, the paraventricular nucleus, or corticotropin-releasing hormone (CRH) neurons and compared them with wild-type controls or isolated knockout groups. In addition to body weight, food intake, energy expenditure, insulin sensitivity, fat/lean mass distribution, and plasma corticosterone levels, we also performed transcriptomic analysis of CRH neurons and assessed their response to melanocortinergic stimulation., Results: Similar to global double-knockout models, deletion of GRs and MRs specifically in mature CRH neurons resulted in obesity. Importantly, the latter was accompanied by insulin resistance, but not increased plasma corticosterone levels. Transcriptomic analysis of these neurons revealed upregulation of several genes involved in postsynaptic signal transduction, including the Ptk2b gene, which encodes proline-rich tyrosine kinase 2. Knockout of both nuclear receptors leads to upregulation of Ptk2b in CRH neurons, which results in their diminished responsiveness to melanocortinergic stimulation., Conclusions: Our data demonstrate the functional redundancy of GRs and MRs in CRH neurons to maintain energy homeostasis and prevent obesity. Simultaneous targeting of both receptors might represent an unprecedented approach to counteract obesity., (© 2024 The Obesity Society.)

Abscisic acid (ABA) is a crucial plant hormone that is naturally produced in various mammalian tissues and holds significant potential as a therapeutic molecule in humans. ABA is selected for this study due to its known roles in essential human metabolic processes, such as glucose homeostasis, immune responses, cardiovascular system, and inflammation regulation. Despite its known importance, the molecular mechanism underlying ABA's action remain largely unexplored. This study employed computational techniques to identify potential human ABA receptors. We screened 64 candidate molecules using online servers and performed molecular docking to assess binding affinity and interaction types with ABA. The stability and dynamics of the best complexes were investigated using molecular dynamics simulation over a 100 ns time period. Root mean square fluctuations (RMSF), root mean square deviation (RMSD), solvent-accessible surface area (SASA), radius of gyration (Rg), free energy landscape (FEL), and principal component analysis (PCA) were analyzed. Next, the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method was employed to calculate the binding energies of the complexes based on the simulated data. Our study successfully pinpointed four key receptors responsible for ABA signaling (androgen receptor, glucocorticoid receptor, mineralocorticoid receptor, and retinoic acid receptor beta) that have a strong affinity for binding with ABA and remained structurally stable throughout the simulations. The simulations with Hydralazine as an unrelated ligand were conducted to validate the specificity of the identified receptors for ABA. The findings of this study can contribute to further experimental validation and a better understanding of how ABA functions in humans., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Patients with salt-wasting congenital adrenal hyperplasia (SW-CAH) usually show pronounced impairment of aldosterone secretion and, therefore, also require mineralocorticoid replacement. While a lot of research and discussion focusses on the glucocorticoid therapy in SW-CAH to replace the missing cortisol and to control adrenal androgen excess, very little research is dealing with mineralocorticoid replacement. However, recent data demonstrated an increased cardiovascular risk in adult CAH patients urging to reflect also on the current mineralocorticoid replacement therapy. In this review, we explain the role and function of the mineralocorticoid receptor, its ligands and inhibitors and its relevance for the therapy of patients with SW-CAH. We performed an extensive literature search and present data on mineralocorticoid therapy in SW-CAH patients as well as clinical advice how to monitor and optimise mineralocorticoid replacement therapy., (© 2023 The Authors. Clinical Endocrinology published by John Wiley & Sons Ltd.)

Due to alternative splicing in an ancestral DNA-binding domain (DBD) of the mineralocorticoid receptor (MR), humans contain two almost identical MR transcripts with either 984 amino acids (MR-984) or 988 amino acids (MR-988), in which their DBDs differ by only four amino acids, Lys,Cys,Ser,Trp (KCSW). Human MRs also contain mutations at two sites, codons 180 and 241, in the amino terminal domain (NTD). Together, there are five distinct full-length human MR genes in GenBank. Human MR-984, which was cloned in 1987, has been extensively studied. Human MR-988, cloned in 1995, contains KCSW in its DBD. Neither this human MR-988 nor the other human MR-988 genes have been studied for their response to aldosterone and other corticosteroids. Here, we report that transcriptional activation of human MR-988 by aldosterone is increased by about 50 % compared to activation of human MR-984 in HEK293 cells transfected with the TAT3 promoter, while the half-maximal response (EC50) is similar for aldosterone activation of MR-984 and MR-988. Transcriptional activation of human MR also depends on the amino acids at codons 180 and 241. Interestingly, in HEK293 cells transfected with the MMTV promoter, transcriptional activation by aldosterone of human MR-988 is similar to activation of human MR-984, indicating that the promoter has a role in the regulation of the response of human MR-988 to aldosterone. The physiological responses to aldosterone and other corticosteroids in humans with MR genes containing KCSW and with differences at codons 180 and 241 in the NTD warrant investigation., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The mineralocorticoid receptor (MR, NR3C2) mediates ion and water homeostasis in epithelial cells of the distal nephron and other tissues. Aldosterone, the prototypical mineralocorticoid, regulates electrolyte and fluid balance. Cortisol binds to MR with equal affinity to aldosterone, but many MR-expressing tissues inactivate cortisol to cortisone via 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2). Dysregulated MR activation contributes to direct cardiovascular tissue insults. Besides aldosterone and cortisol, a variety of MR agonists and/or HSD11B2 inhibitors are putative players in the pathophysiology of low-renin hypertension (LRH), and cardiovascular and metabolic pathology. We developed an in vitro human MR (hMR) model, to facilitate screening for MR agonists, antagonists, and HSD11B2 inhibitors. The CV1 monkey kidney cells were transduced with lentivirus to stably express hMR and an MR-responsive gaussia luciferase gene. Clonal populations of MR-expressing cells (CV1-MRluc) were further transduced to express HSD11B2 (CV1-MRluc-HSD11B2). CV1-MRluc and CV1-MRluc-HSD11B2 cells were treated with aldosterone, cortisol, 11-deoxycorticosterone (DOC), 18-hydroxycorticosterone (18OHB), 18-hydroxycortisol (18OHF), 18-oxocortisol (18oxoF), progesterone, or 17-hydroxyprogesterone (17OHP). In CV1-MRLuc cells, aldosterone and DOC displayed similar potency (EC50: 0.45 nM and 0.30 nM) and maximal response (31- and 23-fold increase from baseline) on hMR; 18oxoF and 18OHB displayed lower potency (19.6 nM and 56.0 nM, respectively) but similar maximal hMR activation (25- and 27-fold increase, respectively); cortisol and corticosterone exhibited higher maximal responses (73- and 52-fold, respectively); 18OHF showed no MR activation. Progesterone and 17OHP inhibited aldosterone-mediated MR activation. In the MRluc-HSD11B2 model, the EC50 of cortisol for MR activation increased from 20 nM (CV1-MRLuc) to ∼2000 nM, while the EC50 for aldosterone remained unchanged. The addition of 18β-glycyrrhetinic acid (18β-GA), a HSD11B2 inhibitor, restored the potency of cortisol back to ∼70 nM in CV1-hMRLuc-HSD11B2 cells. Together, these two cell models will facilitate the discovery of novel MR-modulators, informing MR-mediated pathophysiology mechanisms and drug development efforts., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest. (A) Dose-response curves of 6 endogenous steroids on hMR activation. Calculated maximum fold activation (B) and EC50 (C) for hMR activation. hMR, human mineralocorticoid receptor; 11DOC, 11-Deoxycorticosterone; 18OHB, 18-hydroxycorticosterone. Results are shown as mean ± standard deviation (SD) of three independent replicates. *p<0.05; **p<0.01; ***p<0.001; NS, No statistically significance., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Mineralocorticoid receptor (MR) induces cardiac inflammation cooperatively with nuclear factor-κB and signal transducer and activator of transcription 3 (STAT3); MR blockers exert anti-inflammatory effects. However, the underlying mechanism remains unclear. We investigated the anti-inflammatory effect of esaxerenone, a novel MR blocker, in experimental myocardial infarction (MI) and its underlying mechanisms., Methods and Results: Male C57BL/6J mice subjected to ligation of the left anterior descending artery were randomly assigned to either the vehicle or esaxerenone group. Esaxerenone was provided with a regular chow diet. The mice were euthanized at either 4 or 15 days after MI. Cardiac function, fibrosis, and inflammation were evaluated. Esaxerenone significantly improved cardiac function and attenuated cardiac fibrosis at 15 days after MI independently of its antihypertensive effect. Inflammatory cell infiltration, inflammatory-related gene expression, and elevated serum interleukin-6 levels at 4 days after MI were significantly attenuated by esaxerenone. In vitro experiments using mouse macrophage-like cell line RAW264.7 cells demonstrated that esaxerenone- and spironolactone-attenuated lipopolysaccharide-induced interleukin-6 expression without altering the posttranslational modification and nuclear translocation of p65 and STAT3. Immunoprecipitation assays revealed that MR interacted with both p65 and STAT3 and enhanced the p65-STAT3 interaction, leading to a subsequent increase in interleukin-6 promoter activity, which was reversed by esaxerenone., Conclusions: Esaxerenone ameliorated postinfarct remodeling in experimental MI through its anti-inflammatory properties exerted by modulating the transcriptional activity of the MR-p65-STAT3 complex. These results suggest that the MR-p65-STAT3 complex can be a novel therapeutic target for treating MI.

Aldosterone is a mineralocorticoid hormone involved in controlling electrolyte balance, blood pressure, and cellular signaling. It plays a pivotal role in cardiovascular and metabolic physiology. Excess aldosterone activates mineralocorticoid receptors, leading to subsequent inflammatory responses, increased oxidative stress, and tissue remodeling. Various mechanisms have been reported to link aldosterone with cardiovascular and metabolic diseases. However, mitochondria, responsible for energy generation through oxidative phosphorylation, have received less attention regarding their potential role in aldosterone-related pathogenesis. Excess aldosterone leads to mitochondrial dysfunction, and this may play a role in the development of cardiovascular and metabolic diseases. Aldosterone has the potential to affect mitochondrial structure, function, and dynamic processes, such as mitochondrial fusion and fission. In addition, aldosterone has been associated with the suppression of mitochondrial DNA, mitochondria-specific proteins, and ATP production in the myocardium through mineralocorticoid receptor, nicotinamide adenine dinucleotide phosphate oxidase, and reactive oxygen species pathways. In this review, we explore the mechanisms underlying aldosterone-induced cardiovascular and metabolic mitochondrial dysfunction, including mineralocorticoid receptor activation and subsequent inflammatory responses, as well as increased oxidative stress. Furthermore, we review potential therapeutic targets aimed at restoring mitochondrial function in the context of aldosterone-associated pathologies. Understanding these mechanisms is vital, as it offers insights into novel therapeutic strategies to mitigate the impact of aldosterone-induced mitochondrial dysfunction, thereby potentially improving the outcomes of individuals affected by cardiovascular and metabolic disorders.

Diabetes mellitus is one of the leading causes of chronic kidney disease and its progression to end-stage kidney disease (ESKD). Diabetic kidney disease (DKD) is characterized by glomerular hypertrophy, hyperfiltration, inflammation, and the onset of albuminuria, together with a progressive reduction in glomerular filtration rate. This progression is further accompanied by tubulointerstitial inflammation and fibrosis. Factors such as genetic predisposition, epigenetic modifications, metabolic derangements, hemodynamic alterations, inflammation, and inappropriate renin-angiotensin-aldosterone system (RAAS) activity contribute to the onset and progression of DKD. In this context, decades of work have focused on glycemic and blood pressure reduction strategies, especially targeting the RAAS to slow disease progression. Although much of the work has focused on targeting angiotensin II, emerging data support that the mineralocorticoid receptor (MR) is integral in the development and progression of DKD. Molecular mechanisms linked to the underlying pathophysiological changes derived from MR activation include vascular endothelial and epithelial cell responses to oxidative stress and inflammation. These responses lead to alterations in the microcirculatory environment, the abnormal release of extracellular vesicles, gut dysbiosis, epithelial-mesenchymal transition, and kidney fibrosis. Herein, we present recent experimental and clinical evidence on the MR in DKD onset and progress along with new MR-based strategies for the treatment and prevention of DKD.

The mineralocorticoid receptor (MR/NR3C2) is a member of the family of steroid receptors (SR) which also includes the estrogen receptor (ER), progesterone receptor (PR), androgen receptor (AR) and glucocorticoid receptor (GR). They function primarily as nuclear receptors to regulate gene expression. While the other steroid hormone receptors are known to play important roles in the pathogenesis and progression of many cancers, relatively little is understood about the role of MR in cancer biology. This review focuses on examining new insights into the potential roles and mechanisms of action of MR in cancers., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Stress and inflammation are risk factors for schizophrenia. Chronic psychosocial stress is associated with subcortical hyperdopaminergia, a core feature of schizophrenia. Hyperdopaminergia arises from midbrain neurons, leading us to hypothesise that changes in stress response pathways may occur in this region. To identify whether transcriptional changes in glucocorticoid and mineralocorticoid receptors (NR3C1/GR, NR3C2/MR) or other stress signalling molecules (FKBP4, FKBP5) exist in schizophrenia midbrain, we measured gene expression in the human brain (N = 56) using qRT-PCR. We assessed whether alterations in these mRNAs were related to previously identified high/low inflammatory status. We investigated relationships between stress-related transcripts themselves, and between FKBP5 mRNA, dopaminergic, and glial cell transcripts in diagnostic and inflammatory subgroups. Though unchanged by diagnosis, GR mRNA levels were reduced in high inflammatory compared to low inflammatory schizophrenia cases (p = 0.026). We found no effect of diagnosis or inflammation on MR mRNA. FKBP4 mRNA was decreased and FKBP5 mRNA was increased in schizophrenia (p < 0.05). FKBP5 changes occurred in high inflammatory (p < 0.001), whereas FKBP4 changes occurred in low inflammatory schizophrenia cases (p < 0.05). The decrease in mRNA encoding the main stress receptor (GR), as well as increased transcript levels of the stress-responsive negative regulator (FKBP5), may combine to blunt the midbrain response to stress in schizophrenia when neuroinflammation is present. Negative correlations between FKBP5 mRNA and dopaminergic transcripts in the low inflammatory subgroup suggest higher levels of FKBP5 mRNA may also attenuate dopaminergic neurotransmission in schizophrenia even when inflammation is absent. We report alterations in GR-mediated stress signalling in the midbrain in schizophrenia., Competing Interests: Declaration of competing interest As required for submission of this manuscript to Journal of Psychiatric Research, we confirm that none of the authors listed on this manuscript have any conflicts of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Irisin, as a myokine, plays a protective role against cardiovascular disease, including myocardial infarction, atherosclerosis and hypertension. However, whether irisin attenuates salt-sensitive hypertension and the related underlying mechanisms is unknown., Methods: Male Dahl salt-resistant (DSR) and Dahl salt-sensitive (DSS) (12 weeks) rats were fed a high salt diet (8% NaCl) with or without irisin treatment by intraperitoneal injection for 8 weeks., Results: Compared with DSR rats, DSS rats showed higher systolic blood pressure (SBP), impaired natriuresis and diuresis and renal dysfunction. In addition, it was accompanied by downregulation of renal p-AMPKα and upregulation of renal RAC1 and nuclear mineralocorticoid receptor (MR). Irisin intervention could significantly up-regulated renal p-AMPKα level and down-regulated renal RAC1-MR signal, thereby improving renal sodium excretion and renal function, and ultimately reducing blood pressure in DSS rats. Ex vivo treatment with irisin reduced the expression of RAC1 and nuclear MR in primary renal distal convoluted tubule cells from DSS rats and the effects of irisin were abolished by cotreatment of compound C (AMPK inhibitor), indicating that the regulation of RAC1-MR signals by irisin depended on the activation of AMPK., Conclusions: Irisin administration lowered salt-sensitive hypertension through regulating RAC1-MR signaling via activation of AMPK, which may be a promising therapeutic approach for salt-sensitive hypertension.

The mineralocorticoid receptor (MR) is a member of the nuclear receptor family that was initially identified to regulate blood pressure through its ability to modulate kidney sodium handling in response to aldosterone. MR can be regulated by signals other than aldosterone; however, the detailed mechanisms remain to be elucidated. We found that MR is controlled in a Rho-associated coiled-coil-containing protein kinase 2 (ROCK2)-dependent manner. Mice with a specific deletion of ROCK2 in the kidney tubules showed decreased MR expression levels and increased urinary excretion of sodium. Mechanistically, signal transducer and activator of transcription 3 (STAT3) is a key molecule that mediates MR expression in these mice. This study highlights an important role of tubular ROCK2 in electrolyte homeostasis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The mineralocorticoid and glucocorticoid receptors (MR and GR, respectively) are members of the steroid receptor subfamily of nuclear receptors. Their main function is to act as ligand-activated transcription factors, transducing the effects of corticosteroid hormones (aldosterone and glucocorticoids) by modulating gene expression. Corticosteroid signaling is essential for homeostasis and adaptation to different forms of stress. GR responds to glucocorticoids by regulating genes involved in development, metabolism, immunomodulation and brain function. MR is best known for mediating the effects of aldosterone, a key hormone controlling electrolyte and water homeostasis. In addition to aldosterone, MR binds glucocorticoids (cortisol and corticosterone) with equally high affinity. This ligand promiscuity has important repercussions to understand MR function, as well as glucocorticoid signaling. MR and GR share significant sequence and structural similarities, regulate overlapping sets of genes and are able to interact forming heteromeric complexes. However, the precise role of these heteromers in regulating corticosteroid-regulated transcriptional outcomes remains an open question. In this review, we examine the evidence supporting MR-GR heteromerization, the molecular determinants of complex formation and their possible role in differential regulation of transcription in different cellular contexts and ligand availability., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Cortisol hormone is considered the main corticosteroid in fish stress, acting through glucocorticoid (GR) or mineralocorticoid (MR) receptor. The 11-deoxycorticosterone (DOC) corticosteroid is also secreted during stress and could complement the cortisol effects, but this still not fully understood. Hence, we evaluated the early transcriptomic response of rainbow trout (Oncorhynchus mykiss) liver by DOC through GR or MR. Thirty juvenile trout were pretreated with an inhibitor of endogenous cortisol synthesis (metyrapone) by intraperitoneal injection in presence or absence of GR (mifepristone) and MR (eplerenone) pharmacological antagonists for one hour. Then, fish were treated with a physiological DOC dose or vehicle (DMSO-PBS1X as control) for three hours (n = 5 per group). We measured several metabolic parameters in plasma, together with the liver glycogen content. Additionally, we constructed cDNA libraries from liver of each group, sequenced by HiseqX Illumina technology and then analyzed by RNA-seq. Plasma pyruvate and cholesterol levels decreased in DOC-administered fish and only reversed by eplerenone. Meanwhile, DOC increased liver glycogen contents depending on both corticosteroid receptor pathways. RNA-seq analysis revealed differential expressed transcripts induced by DOC through GR (448) and MR (1901). The enriched biological processes to both were mainly related to stress response, protein metabolism, innate immune response and carbohydrates metabolism. Finally, we selected sixteen genes from enriched biological process for qPCR validation, presenting a high Pearson correlation (0.8734 average). These results describe novel physiological effects of DOC related to early metabolic and transcriptomic responses in fish liver and differentially modulated by MR and GR., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Mineralocorticoid receptor antagonists (MRAs) are one of the renin-angiotensin-aldosterone system inhibitors widely used in clinical practice. While spironolactone and eplerenone have a long-standing profile in clinical medicine, finerenone is a novel agent within the MRA class. It has a higher specificity for mineralocorticoid receptors, eliciting less pronounced adverse effects. Although approved for clinical use in patients with chronic kidney disease and heart failure, intensive non-clinical research aims to further elucidate its mechanism of action, including dose-related selectivity. Within the field, animal models remain the gold standard for non-clinical testing of drug pharmacological and toxicological properties. Their role, however, has been challenged by recent advances in in vitro models, mainly through sophisticated analytical tools and developments in data analysis. Currently, in vitro models are gaining momentum as possible platforms for advanced pharmacological and pathophysiological studies. This article focuses on past, current, and possibly future in vitro cell models research with clinically relevant MRAs.

Excessive activation of the mineralocorticoid receptor (MR) is implicated in cardiovascular and renal disease. Decreasing MR activation with MR antagonists (MRA) is effective to slow chronic kidney disease (CKD) progression and its cardiovascular comorbidities in animal models and patients. The present study evaluates the effects of the MR modulator balcinrenone and the MRA eplerenone on kidney damage in a metabolic CKD mouse model combining nephron reduction and a 60% high-fat diet. Balcinrenone and eplerenone prevented the progression of renal damages, extracellular matrix remodeling and inflammation to a similar extent. We identified a novel mechanism linking MR activation to the renal proteoglycan deposition and inflammation via the TLR4 pathway activation. Balcinrenone and eplerenone similarly blunted this pathway activation., (© 2024 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Multiple sclerosis (MS) is associated with alterations in neuroendocrine function, primarily the hypothalamic-pituitary-adrenal axis, including lower expression of the glucocorticoid receptor (GR) and its target genes in peripheral blood mononuclear cells (PBMC) or full blood. We previously found reduced mineralocorticoid receptor (MR) expression in MS patients' peripheral blood. MS is being treated with a widening variety of disease-modifying treatments (DMT), some of which have similar efficacy but different mechanisms of action; body-fluid biomarkers to support the choice of the optimal initial DMT and/or to indicate an unsatisfactory response before clinical activity are unavailable. Using cell culture of volunteers' PBMCs and subsequent gene expression analysis (microarray and qPCR validation), we identified the mRNA expression of OTUD1 to represent MR signaling. The MR and MR target gene expression levels were then measured in full blood samples. In 119 MS (or CIS) patients, the expression of both MR and OTUD1 was lower than in 42 controls. The expression pattern was related to treatment, with the MR expression being particularly low in patients treated with fingolimod. While MR signaling may be involved in the therapeutic effects of some disease-modifying treatments, MR and OTUD1 expression can complement the neuroendocrine assessment of MS disease course. If confirmed, such assessment may support clinical decision-making.

Hypertension is a significant risk factor for microangiopathy and cardiovascular complications in diabetic patients. The efficacy of mineralocorticoid receptor (MR) antagonists in impeding the advancement of diabetic nephropathy, along with the reduction in active renin concentration observed in diabetic retinopathy, strongly implies the involvement of MR overactivation in diabetic complications. This review provides a comprehensive review of various mechanisms proposed for MR overactivation in diabetes mellitus. In particular, it focuses on post-translational MR modifications, including O-linked N-acetylglucosamine modification and phosphorylation, which have been implicated in MR protein stabilization and overactivation under conditions of high glucose. Given the role of MR overactivation in hyperglycemia, it emerges as a promising therapeutic target for preventing diabetic complications. Post-translational modifications (PTMs), such as O-GlcNAcylation and phosphorylation, are related to MR overactivation in diabetes and metabolic syndrome. Aldosterone binding promotes the proteasomal degradation of MR. Under conditions of high glucose, O-GlcNAcylation, and PKCβ-mediated MR phosphorylation are increased. Salt loading and oxidative stress also increase MR phosphorylation through the EGER/ERK pathway. PTMs inhibit ubiquitin attachment to the MR and interfere with the receptor's aldosterone-induced proteasomal degradation. Consequently, they increase the sensitivity of the MR to aldosterone and exacerbate aldosterone-associated complications., (© 2024. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

Over the past decades, research has clearly established the important role of the mineralocorticoid receptor (MR) in both renal and extra-renal tissues. Recently, caveolin-1 (Cav-1) has emerged as a mediator of MR signaling in several tissues, with implications on cardiovascular and metabolic dysfunction. The main structural component of caveolae (plasma membrane invaginations with diverse functions), Cav-1 is a modulator of cardiovascular function, cellular glucose, and lipid homeostasis, via its effects on signal transduction pathways that mediate inflammatory responses and oxidative stress. In this review, we present evidence indicating an overlap between the roles of the MR and Cav-1 in cardiometabolic disease and the relevant signaling pathways involved. Furthermore, we discuss the potential use of Cav-1 as a biomarker and/or target for MR-mediated dysfunction.

Reactive astrocytes are important pathophysiologically and synthesize neurosteroids. We observed that LPS increased immunoreactive TLR4 and key steroidogenic enzymes in cortical astrocytes of rats and investigated whether corticosteroids are produced and mediate astrocytic TLR4-dependent innate immune responses. We found that LPS increased steroidogenic acute regulatory protein (StAR) and StAR-dependent aldosterone production in purified astrocytes. Both increases were blocked by the TLR4 antagonist TAK242. LPS also increased 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) and corticosterone production, and both were prevented by TAK242 and by siRNAs against 11β-HSD1, StAR, or aldosterone synthase (CYP11B2). Knockdown of 11β-HSD1, StAR, or CYP11B2 or blocking either mineralocorticoid receptors (MR) or glucocorticoid receptors (GR) prevented dephosphorylation of p-Ser 9 GSK-3β, activation of NF-κB, and the GSK-3β-dependent increases of C3, IL-1β, and TNF-α caused by LPS. Exogenous aldosterone mimicked the MR- and GSK-3β-dependent pro-inflammatory effects of LPS in astrocytes, but corticosterone did not. Supernatants from astrocytes treated with LPS reduced MAP2 and viability of cultured neurons except when astrocytic StAR or MR was inhibited. In adrenalectomized rats, intracerebroventricular injection of LPS increased astrocytic TLR4, StAR, CYP11B2, and 11β-HSD1, NF-κB, C3 and IL-1β, decreased astrocytic p-Ser 9 GSK-3β in the cortex and was neurotoxic, except when spironolactone was co-injected, consistent with the in vitro results. LPS also activated NF-κB in some NeuN + and CD11b + cells in the cortex, and these effects were prevented by spironolactone. We conclude that intracrine aldosterone may be involved in the TLR4-dependent innate immune responses of astrocytes and can trigger paracrine effects by activating astrocytic MR/GSK-3β/NF-κB signaling., (© 2024 Federation of American Societies for Experimental Biology.)

One of the initiating events in preeclampsia (PE) is placental ischemia. Rodent models of placental ischemia do not present with vascular endothelial dysfunction, a hallmark of PE. We previously demonstrated a role for leptin in endothelial dysfunction in pregnancy in the absence of placental ischemia. We hypothesized that placental ischemia requires hyperleptinemia and endothelial mineralocorticoid receptor (ECMR) expression to induce PE-associated endothelial dysfunction in pregnant mice. We induced placental ischemia via the reduced uterine perfusion pressure (RUPP) procedure in pregnant ECMR-intact ( ECMR +/+ ) and ECMR deletion ( ECMR -/- ) mice at gestational day (GD) 13 . ECMR +/+ RUPP pregnant mice also received concurrent leptin infusion via miniosmotic pump (0.9 mg/kg/day). RUPP increased blood pressure via radiotelemetry and decreased fetal growth in ECMR +/+ pregnant mice. Both increases in blood pressure and reduced fetal growth were abolished in RUPP ECMR -/- mice. Placental ischemia did not decrease endothelial-dependent relaxation to acetylcholine (ACh) but increased phenylephrine (Phe) contraction in mesenteric arteries of pregnant mice, which was ablated by ECMR deletion. Addition of leptin to RUPP mice significantly reduced ACh relaxation in ECMR +/+ pregnant mice, accompanied by an increase in soluble FMS-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PLGF) ratio. In conclusion, our data indicate that high leptin levels drive endothelial dysfunction in PE and that ECMR is required for clinical characteristics of hypertension and fetal growth restriction in placental ischemia PE. Collectively, we show that both ECMR and leptin play a role to mediate PE. NEW & NOTEWORTHY Leptin is a key feature of preeclampsia that initiates vascular endothelial dysfunction in preeclampsia characterized by placental ischemia. Endothelial mineralocorticoid receptor (ECMR) deletion in placental ischemia protects pregnant mice from elevations in blood pressure and fetal growth restriction in pregnancy. Increases in leptin production mediate the key pathological feature of endothelial dysfunction in preeclampsia in rodents. ECMR activation contributes to the increase in blood pressure and fetal growth restriction in preeclampsia.

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.

Post-traumatic stress disorder (PTSD) is a mental illness that can occur in individuals who have experienced trauma. Current treatments for PTSD, typically serotonin reuptake inhibitors, have limited effectiveness for patients and often cause serious adverse effects. Therefore, a novel class of treatment with better pharmacological profile is necessary. D-Pinitol has been reported to be effective for depression and anxiety disorders, but there are no reports associated with PTSD. In the present study, we investigated the effects of D-pinitol in a mouse model of PTSD induced by a single prolonged stress (SPS) protocol. We examined the therapeutic effects of D-pinitol on emotional and cognitive impairments in the SPS mouse model. We also investigated the effects of D-pinitol on fear memory formation. Mineralocorticoid receptor transactivation assay, Western blot, and quantitative PCR were employed to investigate how D-pinitol exerts its pharmacological activities. D-Pinitol ameliorated PTSD-like behaviors in a SPS mouse model. D-Pinitol also normalized the increased mRNA expression levels and protein levels of the mineralocorticoid receptor in the amygdala. A mineralocorticoid receptor agonist reversed the effects of D-pinitol on fear extinction and recall, and the antagonistic property of D-pinitol against the mineralocorticoid receptor was confirmed in vitro. Our findings suggest that D-pinitol could serve as a potential therapeutic agent for PTSD due to its antagonistic effect on the mineralocorticoid receptor., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this study to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Patients with primary aldosteronism have an increased risk of developing cardiovascular disease. The response to mineralocorticoid receptor antagonists varies among individuals, indicating diverse mineralocorticoid receptor activities in these patients. This study explored the factors linked to the efficacy of blood pressure reduction through mineralocorticoid receptor antagonists in patients with primary aldosteronism. We examined the relationship between the reduction in blood pressure and patient characteristics in a group of 41 patients with primary aldosteronism (24 males, mean age 55 ± 13 years, including 34 patients diagnosed with bilateral primary aldosteronism) before and after undergoing treatment with mineralocorticoid receptor antagonists. Significant reductions in office blood pressure were observed 3 and 6 months after treatment initiation. Single correlation analyses showed that the urinary chloride-to-potassium ratio displayed the strongest positive association with blood pressure reduction, surpassing plasma aldosterone concentration, plasma renin activity, and urinary sodium-to-potassium ratio, at 3 and 6 months. Multiple correlation analyses revealed a consistent and independent positive correlation between the urinary chloride-to-potassium ratio and blood pressure reduction at 3 and 6 months. The optimal threshold for the urinary chloride-to-potassium ratio with respect to its ability to lower blood pressure, was determined as 3.18. These results imply that the urinary chloride-to-potassium ratio may be independently associated with the effectiveness of blood pressure reduction facilitated by mineralocorticoid receptor antagonists. Moreover, it could potentially serve as a valuable predictor of the effectiveness of these agents and function as an indicator of endogenous mineralocorticoid receptor activity in patients with primary aldosteronism., (© 2024. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

Maternal type 2 diabetes mellitus (T2DM) has been shown to result in foetal programming of the hypothalamic-pituitary-adrenal (HPA) axis, leading to adverse foetal outcomes. T2DM is preceded by prediabetes and shares similar pathophysiological complications. However, no studies have investigated the effects of maternal prediabetes on foetal HPA axis function and postnatal offspring development. Hence, this study investigated the effects of pregestational prediabetes on maternal HPA axis function and postnatal offspring development. Pre-diabetic (PD) and non-pre-diabetic (NPD) female Sprague Dawley rats were mated with non-prediabetic males. After gestation, male pups born from the PD and NPD groups were collected. Markers of HPA axis function, adrenocorticotropin hormone (ACTH) and corticosterone, were measured in all dams and pups. Glucose tolerance, insulin and gene expressions of mineralocorticoid (MR) and glucocorticoid (GR) receptors were further measured in all pups at birth and their developmental milestones. The results demonstrated increased basal concentrations of ACTH and corticosterone in the dams from the PD group by comparison to NPD. Furthermore, the results show an increase basal ACTH and corticosterone concentrations, disturbed MR and GR gene expression, glucose intolerance and insulin resistance assessed via the Homeostasis Model Assessment (HOMA) indices in the pups born from the PD group compared to NPD group at all developmental milestones. These observations reveal that pregestational prediabetes is associated with maternal dysregulation of the HPA axis, impacting offspring HPA axis development along with impaired glucose handling.

Klotho regulates many pathways in the aging process, but it remains unclear how it is physiologically regulated. Because Klotho is synthesized, cleaved, and released from the kidney; activates the chief urinary K + secretion channel (ROMK) and stimulates urinary K + secretion, we explored if Klotho protein is regulated by dietary K + and the potassium-regulatory hormone, Aldosterone. Klotho protein along the nephron was evaluated in humans and in wild-type (WT) mice; and in mice lacking components of Aldosterone signaling, including the Aldosterone-Synthase KO (AS-KO) and the Mineralocorticoid-Receptor KO (MR-KO) mice. We found the specific cells of the distal nephron in humans and mice that are chief sites of regulated K + secretion have the highest Klotho protein expression along the nephron. WT mice fed K + -rich diets increased Klotho expression in these cells. AS-KO mice exhibit normal Klotho under basal conditions but could not upregulate Klotho in response to high-K + intake in the K + -secreting cells. Similarly, MR-KO mice exhibit decreased Klotho protein expression. Together, i) Klotho is highly expressed in the key sites of regulated K + secretion in humans and mice, ii) In mice, K + -rich diets increase Klotho expression specifically in the potassium secretory cells of the distal nephron, iii) Aldosterone signaling is required for Klotho response to high K + intake., (© 2024. The Author(s).)

Inflammation and fibrosis often occur in the kidney after acute injury, resulting in chronic kidney disease and consequent renal failure. Recent studies have indicated that lymphangiogenesis can drive renal inflammation and fibrosis in injured kidneys. However, whether and how this pathogenesis affects the contralateral kidney remain largely unknown. In our study, we uncovered a mechanism by which the contralateral kidney responded to injury. We found that the activation of mineralocorticoid receptors and the increase in vascular endothelial growth factor C in the contralateral kidney after unilateral ureteral obstruction could promote lymphangiogenesis. Furthermore, mineralocorticoid receptor activation in lymphatic endothelial cells resulted in the secretion of myofibroblast markers, thereby contributing to renal fibrosis. We observed that this process could be attenuated by administering the mineralocorticoid receptor blocker eplerenone, which, prevented the development of fibrotic injury in the contralateral kidneys of rats with unilateral ureteral obstruction. These findings offer valuable insights into the intricate mechanisms underlying kidney injury and may have implications for the development of therapeutic strategies to mitigate renal fibrosis in the context of kidney disease., (© 2024. The Author(s).)

After half a century of evidence suggesting the existence of mineralocorticoid receptors (MR) in the vasculature, the advent of technology to specifically knockout the MR from smooth muscle cells (SMCs) in mice has elucidated contributions of SMC-MR to cardiovascular function and disease, independent of the kidney. This review summarizes the latest understanding of the molecular mechanisms by which SMC-MR contributes to (1) regulation of vasomotor function and blood pressure to contribute to systemic and pulmonary hypertension; (2) vascular remodeling in response to hypertension, vascular injury, obesity, and aging, and the impact on vascular calcification; and (3) cardiovascular pathologies including aortic aneurysm, heart valve dysfunction, and heart failure. Data are reviewed from in vitro studies using SMCs and in vivo findings from SMC-specific MR-knockout mice that implicate target genes and signaling pathways downstream of SMC-MR. By regulating expression of the L-type calcium channel subunit Cav1.2 and angiotensin II type-1 receptor, SMC-MR contributes to myogenic tone and vasoconstriction, thereby contributing to systemic blood pressure. MR activation also promotes SMC proliferation, migration, production and degradation of extracellular matrix, and osteogenic differentiation by regulating target genes including connective tissue growth factor, osteopontin, bone morphogenetic protein 2, galectin-3, and matrix metallopeptidase-2. By these mechanisms, SMC-MR promotes disease progression in models of aging-associated vascular stiffness, vascular calcification, mitral and aortic valve disease, pulmonary hypertension, and heart failure. While rarely tested, when sexes were compared, the mechanisms of SMC-MR-mediated disease were sexually dimorphic. These advances support targeting SMC-MR-mediated mechanisms to prevent and treat diverse cardiovascular disorders., Competing Interests: Disclosures None.

Aldosterone is a steroid hormone that primarily acts through activation of the mineralocorticoid receptor (MR), a nuclear receptor responsible for downstream genomic regulation. Classically, activation of the MR in the renal tubular epithelium is responsible for sodium retention and volume expansion, raising systemic blood pressure. However, activation of the MR across a wide distribution of tissue types has been implicated in multiple adverse consequences for cardiovascular, cerebrovascular, renal, and metabolic disease, independent of blood pressure alone. Primary aldosteronism, heart failure, and chronic kidney disease are states of excessive aldosterone production and MR activity where targeting MR activation has had clinical benefits out of proportion to blood pressure lowering. The growing list of established and emerging therapies that target aldosterone and MR activation may provide new opportunities to improve clinical outcomes and enhance cardiovascular and renal health.

Colorectal cancer (CRC) is a formidable threat to human well-being, characterized by a largely enigmatic occurrence and progression mechanism. A growing body of literature has underscored the potential influence of propofol, a frequently administered anesthetic, on clinical outcomes in malignant tumor patients. However, the precise molecular mechanisms underlying the impact of propofol on the progression of CRC have yet to be fully elucidated. This study reveals a notable upregulation of LINC01133 expression in CRC cells subsequent to propofol treatment, which is mediated by FOXO1. Subsequently, a series of experiments were conducted to elucidate the role and mechanisms underlying propofol-induced LINC01133 in CRC development. Our study uncovers that the upregulation of LINC01133 exerts a substantial inhibitory effect on the proliferation, migration, and invasion of CRC cells. Further investigation revealed that LINC01133 can attenuate the proliferation, invasion, and migration of CRC cell lines through the miR-186-5p/NR3C2 axis. Results from in vivo experiments unequivocally demonstrated a significant reduction in the growth rate of subcutaneous implant tumors upon LINC01133 overexpression in CRC cells. These findings posit that propofol induces LINC01133 expression, leading to the inhibition of CRC progression. This revelation offers a novel perspective on propofol's antitumor properties and underscores the potential of LINC01133 as a promising therapeutic target for CRC., (© 2023 Wiley Periodicals LLC.)

Inflammaging, a pro-inflammatory status that characterizes aging and primarily involving macrophages, is a master driver of age-related diseases. Mineralocorticoid receptor (MR) activation in macrophages critically regulates inflammatory and fibrotic processes. However, macrophage-specific mechanisms and the role of the macrophage MR for the regulation of inflammation and fibrotic remodeling in the aging heart have not yet been elucidated. Transcriptome profiling of cardiac macrophages from male/female young (4 months-old), middle (12 months-old) and old (18 and 24 months-old) mice revealed that myeloid cell-restricted MR deficiency prevents macrophage differentiation toward a pro-inflammatory phenotype. Pathway enrichment analysis showed that several biological processes related to inflammation and cell metabolism were modulated by the MR in aged macrophages. Further, transcriptome analysis of aged cardiac fibroblasts revealed that macrophage MR deficiency reduced the activation of pathways related to inflammation and upregulation of ZBTB16, a transcription factor involved in fibrosis. Phenotypic characterization of macrophages showed a progressive replacement of the TIMD4 + MHC-II neg/low macrophage population by TIMD4 + MHC-II int/high and TIMD4 - MHC-II int/high macrophages in the aging heart. By integrating cell sorting and transwell experiments with TIMD4 + /TIMD4 - macrophages and fibroblasts from old MR flox /MR LysMCre hearts, we showed that the inflammatory crosstalk between TIMD4 - macrophages and fibroblasts may imply the macrophage MR and the release of mitochondrial superoxide anions. Macrophage MR deficiency reduced the expansion of the TIMD4 - macrophage population and the emergence of fibrotic niches in the aging heart, thereby protecting against cardiac inflammation, fibrosis, and dysfunction. This study highlights the MR as an important mediator of cardiac macrophage inflammaging and age-related fibrotic remodeling., (© 2024. The Author(s).)

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Myosin phosphatase targeting subunit 2 (MYPT2) is an important subunit of cardiac MLC (myosin light chain) phosphatase, which plays a crucial role in regulating the phosphorylation of MLC to phospho-MLC (p-MLC). A recent study demonstrated mineralocorticoid receptor-related hypertension is associated with RhoA/Rho-associated kinase/MYPT1 signaling upregulation in smooth muscle cells. Our purpose is to investigate the effect of MYPT2 on cardiac function and fibrosis in mineralocorticoid receptor-related hypertension., Methods and Results: HL-1 murine cardiomyocytes were incubated with different concentrations or durations of aldosterone. After 24-hour stimulation, aldosterone increased CTGF (connective tissue growth factor) and MYPT2 and decreased p-MLC in a dose-dependent manner. MYPT2 knockdown decreased CTGF. Cardiac-specific MYPT2-knockout (c-MYPT2 -/- ) mice exhibited decreased type 1 phosphatase catalytic subunit β and increased p-MLC. A disease model of mouse was induced by subcutaneous aldosterone and 8% NaCl food for 4 weeks after uninephrectomy. Blood pressure elevation and left ventricular hypertrophy were observed in both c-MYPT2 -/- and MYPT2 +/+ mice, with no difference in heart weights or nuclear localization of mineralocorticoid receptor in cardiomyocytes. However, c-MYPT2 -/- mice had higher ejection fraction and fractional shortening on echocardiography after aldosterone treatment. Histopathology revealed less fibrosis, reduced CTGF, and increased p-MLC in c-MYPT2 -/- mice. Basal global radial strain and global longitudinal strain were higher in c-MYPT2 -/- than in MYPT2 +/+ mice. After aldosterone treatment, both global radial strain and global longitudinal strain remained higher in c-MYPT2 -/- mice compared with MYPT2 +/+ mice., Conclusions: Cardiac-specific MYPT2 knockout leads to decreased myosin light chain phosphatase and increased p-MLC. MYPT2 deletion prevented cardiac fibrosis and dysfunction in a model of mineralocorticoid receptor-associated hypertension.

The hypothalamic-pituitary-adrenal (HPA) axis coordinates an organism's response to environmental stress. The responsiveness and sensitivity of an offspring's stress response may be shaped not only by stressors encountered in their early post-natal environment but also by stressors in their parent's environment. Yet, few studies have considered how stressors encountered in both of these early life environments may function together to impact the developing HPA axis. Here, we manipulated stressors in the parental and post-natal environments in a population of house sparrows (Passer domesticus) to assess their impact on changes in DNA methylation (and corresponding gene expression) in a suite of genes within the HPA axis. We found that nestlings that experienced early life stress across both life-history periods had higher DNA methylation in a critical HPA axis gene, the glucocorticoid receptor (NR3C1). In addition, we found that the life-history stage when stress was encountered impacted some genes (HSD11B1, NR3C1 and NR3C2) differently. We also found evidence for the mitigation of parental stress by post-natal stress (in HSD11B1 and NR3C2). Finally, by assessing DNA methylation in both the brain and blood, we were able to evaluate cross-tissue patterns. While some differentially methylated regions were tissue-specific, we found cross-tissue changes in NR3C2 and NR3C1, suggesting that blood is a suitable tissue for assessing DNA methylation as a biomarker of early life stress. Our results provide a crucial first step in understanding the mechanisms by which early life stress in different life-history periods contributes to changes in the epigenome of the HPA axis., (© 2024 John Wiley & Sons Ltd.)

The prevailing model of steroid hormone nuclear receptor function assumes ligand-induced homodimer formation followed by binding to DNA hormone response elements (HREs). This model has been challenged by evidence showing that the glucocorticoid receptor (GR) forms tetramers upon ligand and DNA binding, which then drive receptor-mediated gene transactivation and transrepression. GR and the closely-related mineralocorticoid receptors (MR) interact to transduce corticosteroid hormone signaling, but whether they share the same quaternary arrangement is unknown. Here, we used a fluorescence imaging technique, Number & Brightness, to study oligomerization in a cell system allowing real-time analysis of receptor-DNA interactions. Agonist-bound MR forms tetramers in the nucleoplasm and higher order oligomers upon binding to HREs. Antagonists form intermediate-size quaternary arrangements, suggesting that large oligomers are essential for function. Divergence between MR and GR quaternary structure is driven by different functionality of known and new multimerization interfaces, which does not preclude formation of heteromers. Thus, influencing oligomerization may be important to selectively modulate corticosteroid signaling., (© 2023 The Authors. Protein Science published by Wiley Periodicals LLC on behalf of The Protein Society.)

Objective: To characterize the dose-exposure-response effect of spironolactone on biomarkers of the classical and alternative arms of the renin-angiotensin-aldosterone system (RAAS) in healthy dogs., Animals: Ten healthy purpose-bred Beagle dogs., Procedures: Study dogs were randomly allocated to 2 spironolactone dosing groups (2 mg/kg PO q24hr, 4 mg/kg PO q24hr). The dogs received 7-day courses of spironolactone followed by a 14-day washout period in a crossover (AB/BA) design. Angiotensin peptides and aldosterone were measured in serum using equilibrium analysis, and plasma canrenone and 7-α-thiomethyl spironolactone (TMS) were quantified via liquid chromatography-mass spectrometry/mass spectroscopy (LC-MS/MS). Study results were compared before and after dosing and between groups., Results: Following spironolactone treatment, dogs had a significant increase in serum aldosterone concentration (P = 0.07), with no statistical differences between dosing groups. Significant increases in angiotensin II (P = 0.09), angiotensin I (P = 0.08), angiotensin 1-5 (P = 0.08), and a surrogate marker for plasma renin activity (P = 0.06) were detected compared to baseline following spironolactone treatment during the second treatment period only. Overall, changes from baseline did not significantly differ between spironolactone dosages. RAAS analytes were weakly correlated (R < 0.4) with spironolactone dosage and plasma canrenone or plasma TMS. There were no adverse clinical or biochemical effects seen at any spironolactone dosage during treatment., Conclusions: Treatment with spironolactone increased serum aldosterone concentration in healthy dogs and impacted other biomarkers of the classical and alternative arms of the RAAS. There was no difference in effect on the RAAS between 2 and 4 mg/kg/day dosing. Dosage of 4 mg/kg/day was safe and well-tolerated in healthy dogs., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: author EG is an employee of Ceva Sante Animale and authors JLW and JPM have served as consultants for Ceva Sante Animale and have received reimbursement and honoraria for consulting, expert testimony, travel, and service as key opinion leaders. Ceva Sante Animale is a multinational company that performs research, develops, manufactures and supplies vaccines, pharmaceutical medicines and other animal health products, together with the equipment, training, technical support and specialized services to ensure their optimal use. Ceva Sante Animale provided funding for this research. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Masters et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)