Novel Insights into the Role of the Mineralocorticoid Receptor in Human Glioblastoma.
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ABSTRACT:
SUBMITTER: Aldaz P
PROVIDER: S-EPMC8584062 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Vascular calcification, which is common in the elderly and in patients with atherosclerosis, diabetes and chronic renal disease, increases the risk of cardiovascular morbidity and mortality. It is a complex, active and highly regulated cellular process that resembles physiological bone formation. It has previously been established that pharmacological doses of glucocorticoids facilitate arterial calcification. However, the consequences for vascular calcification of endogenous glucocorticoid elevation have yet to be established. Glucocorticoids (cortisol, corticosterone) are released from the adrenal gland, but can also be generated within cells from 11-keto metabolites of glucocorticoids (cortisone, 11-dehydrocorticosterone [11-DHC]) by the enzyme, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). In the current study we hypothesized that endogenous glucocorticoids facilitate vascular smooth muscle cell (VSMC) calcification and investigated the receptor-mediated mechanism underpinning this process. In vitro studies revealed increased phosphate-induced calcification in mouse VSMCs following treatment for 7days with corticosterone (100nM; 7.98 fold; P<0.01), 11-DHC (100nM; 7.14 fold; P<0.05) and dexamethasone (10nM; 7.16 fold; P<0.05), a synthetic glucocorticoid used as a positive control. Inhibition of 11β-HSD isoenzymes by 10μM carbenoxolone reduced the calcification induced by 11-DHC (0.37 fold compared to treatment with 11-DHC alone; P<0.05). The glucocorticoid receptor (GR) antagonist mifepristone (10μM) had no effect on VSMC calcification in response to corticosterone or 11-DHC. In contrast, the mineralocorticoid receptor (MR) antagonist eplerenone (10μM) significantly decreased corticosterone- (0.81 fold compared to treatment with corticosterone alone; P<0.01) and 11-DHC-driven (0.64 fold compared to treatment with 11-DHC alone; P<0.01) VSMC calcification, suggesting this glucocorticoid effect is MR-driven and not GR-driven. Neither corticosterone nor 11-DHC altered the mRNA levels of the osteogenic markers PiT-1, Osx and Bmp2. However, DAPI staining of pyknotic nuclei and flow cytometry analysis of surface Annexin V expression showed that corticosterone induced apoptosis in VSMCs. This study suggests that in mouse VSMCs, corticosterone acts through the MR to induce pro-calcification effects, and identifies 11β-HSD-inhibition as a novel potential treatment for vascular calcification.
| S-EPMC5111541 | biostudies-literature
Project description:Since the mineralocorticoid receptor (MR) was cloned 30 years ago, it has become clear that MR is expressed in extra-renal tissues, including the cardiovascular system, where it is expressed in all cells of the vasculature. Understanding the role of MR in the vasculature has been of particular interest as clinical trials show that MR antagonism improves cardiovascular outcomes out of proportion to changes in blood pressure. The last 30 years of research have demonstrated that MR is a functional hormone-activated transcription factor in vascular smooth muscle cells and endothelial cells. This review summarizes advances in our understanding of the role of vascular MR in regulating blood pressure and vascular function, and its contribution to vascular disease. Specifically, vascular MR contributes directly to blood pressure control and to vascular dysfunction and remodeling in response to hypertension, obesity and vascular injury. The literature is summarized with respect to the role of vascular MR in conditions including: pulmonary hypertension; cerebral vascular remodeling and stroke; vascular inflammation, atherosclerosis and myocardial infarction; acute kidney injury; and vascular pathology in the eye. Considerations regarding the impact of age and sex on the function of vascular MR are also described. Further investigation of the precise molecular mechanisms by which MR contributes to these processes will aid in the identification of novel therapeutic targets to reduce cardiovascular disease (CVD)-related morbidity and mortality.
| S-EPMC5518626 | biostudies-literature
Project description:Mineralocorticoid receptor (MR)-mediated signaling in the brain has been suggested as a protective factor in the development of psychopathology, in particular mood disorders. We recently identified genomic loci at which either MR or the closely related glucocorticoid receptor (GR) binds selectively, and found members of the NeuroD transcription factor family to be specifically associated with MR-bound DNA in the rat hippocampus. We show here using forebrain-specific MR knockout mice that GR binding to MR/GR joint target loci is not affected in any major way in the absence of MR. Neurod2 binding was also independent of MR binding. Moreover, functional comparison with MyoD family members indicates that it is the chromatin remodeling aspect of NeuroD, rather than its direct stimulation of transcription, that is responsible for potentiation of MR-mediated transcription. These findings suggest that NeuroD acts in a permissive way to enhance MR-mediated transcription, and they argue against competition for DNA binding as a mechanism of MR- over GR-specific binding.
| S-EPMC6479562 | biostudies-literature
Project description:Mineralocorticoid receptors (MRs) in the brain play a role in learning and memory, neuronal differentiation, and regulation of the stress response. Within the hippocampus, the highest expression of MRs is in area CA2. CA2 pyramidal neurons have a distinct molecular makeup resulting in a plasticity-resistant phenotype, distinguishing them from neurons in CA1 and CA3. Thus, we asked whether MRs regulate CA2 neuron properties and CA2-related behaviors. Using three conditional knockout methods at different stages of development, we found a striking decrease in multiple molecular markers for CA2, an effect mimicked by chronic antagonism of MRs. Furthermore, embryonic deletion of MRs disrupted afferent inputs to CA2 and enabled synaptic potentiation of the normally LTP-resistant synaptic currents in CA2. We also found that CA2-targeted MR knockout was sufficient to disrupt social behavior and alter behavioral responses to novelty. Altogether, these results demonstrate an unappreciated role for MRs in controlling CA2 pyramidal cell identity and in facilitating CA2-dependent behaviors.
| S-EPMC7234915 | biostudies-literature
Project description:Increased visceral adiposity and hyperglycemia, two characteristics of metabolic syndrome, are also present in conditions of excess glucocorticoids (GCs). GCs are hormones thought to act primarily via the glucocorticoid receptor (GR). GCs are commonly prescribed for inflammatory disorders, yet their use is limited due to many adverse metabolic side effects. In addition to GR, GCs also bind the mineralocorticoid receptor (MR), but there are many conflicting studies as to the exact role of MR in metabolic disease. Using MR knockout mice (MRKO), we find that both white and brown adipose depots form normally when compared to wild-type mice at P5. We created mice with adipocyte-specific deletion of MR (FMRKO) to better understand the role of MR in metabolic dysfunction. Treatment of mice with excess GCs for 4 weeks, via corticosterone in drinking water, induced increased fat mass and glucose intolerance to similar levels in FMRKO and floxed-control mice. Separately, when fed a high-fat diet for 16 weeks, FMRKO mice had reduced body weight, fat mass, and hepatic steatosis, relative to floxed-control mice. Decreased adiposity likely resulted from increased energy expenditure since food intake was not different. RNA sequencing analysis revealed decreased enrichment of genes associated with adipogenesis in inguinal white adipose of FMRKO mice. Differentiation of mouse embryonic fibroblasts (MEFs), showed modestly impaired adipogenesis in MRKO MEFs compared to wild-type, but this was rescued upon the addition of peroxisome proliferator-activated receptor gamma (PPARγ) agonist or PPARγ overexpression. Collectively, these studies provide further evidence supporting the potential value of MR as a therapeutic target for conditions associated with metabolic syndrome. Method (Chow): At six weeks of age mice were maintained on a chow diet (PicoLab® Rodent Diet 20 5053* [20% protein]) for 16 weeks Method (High Fat Diet): 6 week-old mice were fed ab libitum with Teklad TD.88137 (21.2% fat [42% kcal fat], 48.5% carbohydrate [34% sucrose by weight], 17.3% protein, and 0.2% cholesterol by weight) for 16 weeks Method (Corticosterone): 10-11-week-old mice were administered corticosterone via drinking water (100 μg/mL) for 4 weeks, while maintained on a chow diet
2019-11-01 | GSE138632 | GEO
Project description:Elaboration of the oxazolidinedione series led to replacement of the exocyclic amides with substituted benzimidazoles. The structure-activity relationship (SAR) exploration resulted in the discovery of potent and selective nonsteroidal mineralocorticoid receptor (MR) antagonists with significantly improved microsomal stability and pharmacokinetic (PK) profile relative to the HTS hit 1a. One compound 2p possessed comparable efficacy as spironolactone (SPL) at 100 mg/kg (p.o.) in the rat natriuresis model. As such, this series was validated as a lead series for further optimization.
| S-EPMC4416436 | biostudies-literature
Project description:Central serous chorioretinopathy (CSCR) is a vision-threatening eye disease with no validated treatment and unknown pathogeny. In CSCR, dilation and leakage of choroid vessels underneath the retina cause subretinal fluid accumulation and retinal detachment. Because glucocorticoids induce and aggravate CSCR and are known to bind to the mineralocorticoid receptor (MR), CSCR may be related to inappropriate MR activation. Our aim was to assess the effect of MR activation on rat choroidal vasculature and translate the results to CSCR patients. Intravitreous injection of the glucocorticoid corticosterone in rat eyes induced choroidal enlargement. Aldosterone, a specific MR activator, elicited the same effect, producing choroid vessel dilation -and leakage. We identified an underlying mechanism of this effect: aldosterone upregulated the endothelial vasodilatory K channel KCa2.3. Its blockade prevented aldosterone-induced thickening. To translate these findings, we treated 2 patients with chronic nonresolved CSCR with oral eplerenone, a specific MR antagonist, for 5 weeks, and observed impressive and rapid resolution of retinal detachment and choroidal vasodilation as well as improved visual acuity. The benefit was maintained 5 months after eplerenone withdrawal. Our results identify MR signaling as a pathway controlling choroidal vascular bed relaxation and provide a pathogenic link with human CSCR, which suggests that blockade of MR could be used therapeutically to reverse choroid vasculopathy.
| S-EPMC3386817 | biostudies-other
Project description:The novel nonsteroidal mineralocorticoid receptor (MR) antagonist finerenone holds promise to be safe and efficient in the treatment of patients with heart failure and/or chronic kidney disease. However, its effects on vascular function remain elusive.The aim of this study was to determine the functional effect of selective MR antagonism by finerenone in vascular cells in vitro and the effect on vascular remodeling following acute vascular injury in vivo.In vitro, finerenone dose-dependently reduced aldosterone-induced smooth muscle cell (SMC) proliferation, as quantified by BrdU incorporation, and prevented aldosterone-induced endothelial cell (EC) apoptosis, as measured with a flow cytometry based caspase 3/7 activity assay. In vivo, oral application of finerenone resulted in an accelerated re-endothelialization 3 days following electric injury of the murine carotid artery. Furthermore, finerenone treatment inhibited intimal and medial cell proliferation following wire-induced injury of the murine femoral artery 10 days following injury and attenuated neointimal lesion formation 21 days following injury.Finerenone significantly reduces apoptosis of ECs and simultaneously attenuates SMC proliferation, resulting in accelerated endothelial healing and reduced neointima formation of the injured vessels. Thus, finerenone appears to provide favorable vascular effects through restoring vascular integrity and preventing adverse vascular remodeling.
| S-EPMC5605005 | biostudies-other
Project description:BACKGROUND:The remarkable success of clinical trials in mineralocorticoid receptor (MR) inhibition in heart failure has driven research on the physiological and pathological role(s) of nonepithelial MR expression. MR is widely expressed in the cardiovascular system and is a major determinant of endothelial function, smooth muscle tone, vascular remodeling, fibrosis, and blood pressure. An important new dimension is the appreciation of the role MR plays in immune cells and target organ damage in the heart, kidney and vasculature, and in the development of insulin resistance. SUMMARY:The mechanism for MR activation in tissue injury continues to evolve with the evidence to date suggesting that activation of MR results in a complex repertoire of effects involving both macrophages and T cells. MR is an important transcriptional regulator of macrophage phenotype and function. Another important feature of MR activation is that it can occur even with normal or low aldosterone levels in pathological conditions. Tissue-specific conditional models of MR expression in myeloid cells, endothelial cells, smooth muscle cells and cardiomyocytes have been very informative and have firmly demonstrated a critical role of MR as a key pathophysiologic variable in cardiac hypertrophy, transition to heart failure, adipose inflammation, and atherosclerosis. Finally, the central nervous system activation of MR in permeable regions of the blood-brain barrier may play a role in peripheral inflammation. Key Message: Ongoing clinical trials will help clarify the role of MR blockade in conditions, such as atherosclerosis and chronic kidney disease.
| S-EPMC6863172 | biostudies-literature
Project description:AKI is a frequent complication in hospitalized patients. Unfortunately, there is no effective pharmacologic approach for treating or preventing AKI. In rodents, mineralocorticoid receptor (MR) antagonism prevents AKI induced by ischemia-reperfusion (IR). We investigated the specific role of vascular MR in mediating AKI induced by IR. We also assessed the protective effect of MR antagonism in IR-induced AKI in the Large White pig, a model of human AKI. In mice, MR deficiency in smooth muscle cells (SMCs) protected against kidney IR injury. MR blockade by the novel nonsteroidal MR antagonist, finerenone, or genetic deletion of MR in SMCs associated with weaker oxidative stress production. Moreover, ischemic kidneys had higher levels of Rac1-GTP, required for NADPH oxidase activation, than sham control kidneys, and genetic deletion of Rac1 in SMCs protected against AKI. Furthermore, genetic deletion of MR in SMCs blunted the production of Rac1-GTP after IR. Pharmacologic inhibition of MR also prevented AKI induced by IR in the Large White pig. Altogether, we show that MR antagonism, or deletion of the MR gene in SMCs, limited the renal injury induced by IR through effects on Rac1-mediated MR signaling. The benefits of MR antagonism in the pig provide a rational basis for future clinical trials assessing the benefits of this approach in patients with IR-mediated AKI.
| S-EPMC5373452 | biostudies-literature