RESUMEN
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.
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Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Antagonistas de Receptores de Mineralocorticoides , Infarto del Miocardio , Receptores de Mineralocorticoides , Factor de Transcripción STAT3 , Sulfonas , Factor de Transcripción ReIA , Animales , Factor de Transcripción STAT3/metabolismo , Masculino , Receptores de Mineralocorticoides/metabolismo , Receptores de Mineralocorticoides/efectos de los fármacos , Receptores de Mineralocorticoides/genética , Antagonistas de Receptores de Mineralocorticoides/farmacología , Ratones , Infarto del Miocardio/metabolismo , Infarto del Miocardio/patología , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/prevención & control , Infarto del Miocardio/genética , Factor de Transcripción ReIA/metabolismo , Células RAW 264.7 , Sulfonas/farmacología , Transducción de Señal/efectos de los fármacos , Fibrosis , Transcripción Genética/efectos de los fármacos , Miocardio/metabolismo , Miocardio/patología , Antiinflamatorios/farmacología , Interleucina-6/metabolismo , Interleucina-6/genética , PirrolesRESUMEN
Objective: MR (mineralocorticoid receptor) activation associates with increased risk of cardiovascular ischemia while MR inhibition reduces cardiovascular-related mortality and plaque inflammation in mouse atherosclerosis. MR in myeloid cells (My-MR) promotes inflammatory cell infiltration into injured tissues and atherosclerotic plaque inflammation by unclear mechanisms. Here, we examined the role of My-MR in leukocyte trafficking and the impact of sex. Approach and Results: We confirm in vivo that My-MR deletion (My-MR-KO) in ApoE-KO mice decreased plaque size. Flow cytometry revealed fewer plaque macrophages with My-MR-KO. By intravital microscopy, My-MR-KO significantly attenuated monocyte slow-rolling and adhesion to mesenteric vessels and decreased peritoneal infiltration of myeloid cells in response to inflammatory stimuli in male but not female mice. My-MR-KO mice had significantly less PSGL1 (P-selectin glycoprotein ligand 1) mRNA in peritoneal macrophages and surface PSGL1 protein on circulating monocytes in males. In vitro, MR activation with aldosterone significantly increased PSGL1 mRNA only in monocytes from MR-intact males. Similarly, aldosterone induced, and MR antagonist spironolactone inhibited, PSGL1 expression in human U937 monocytes. Mechanistically, aldosterone stimulated MR binding to a predicted MR response element in intron-1 of the PSGL1 gene by ChIP-qPCR. Reporter assays demonstrated that this PSGL1 MR response element is necessary and sufficient for aldosterone-activated, MR-dependent transcriptional activity. Conclusions: These data identify PSGL1 as a My-MR target gene that drives leukocyte trafficking to enhance atherosclerotic plaque inflammation. These novel and sexually dimorphic findings provide insight into increased ischemia risk with MR activation, cardiovascular protection in women, and the role of MR in atherosclerosis and tissue inflammation.
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Aorta Torácica/metabolismo , Enfermedades de la Aorta/metabolismo , Aterosclerosis/metabolismo , Adhesión Celular , Rodamiento de Leucocito , Macrófagos Peritoneales/metabolismo , Glicoproteínas de Membrana/metabolismo , Monocitos/metabolismo , Receptores de Mineralocorticoides/metabolismo , Adulto , Animales , Aorta Torácica/patología , Enfermedades de la Aorta/genética , Enfermedades de la Aorta/patología , Enfermedades de la Aorta/prevención & control , Aterosclerosis/genética , Aterosclerosis/patología , Aterosclerosis/prevención & control , Adhesión Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Células HEK293 , Humanos , Hipoglucemia/tratamiento farmacológico , Hipoglucemia/genética , Hipoglucemia/metabolismo , Rodamiento de Leucocito/efectos de los fármacos , Macrófagos Peritoneales/patología , Masculino , Glicoproteínas de Membrana/genética , Ratones Endogámicos C57BL , Ratones Noqueados para ApoE , Persona de Mediana Edad , Antagonistas de Receptores de Mineralocorticoides/uso terapéutico , Monocitos/efectos de los fármacos , Monocitos/patología , Ensayos Clínicos Controlados Aleatorios como Asunto , Receptores de Mineralocorticoides/efectos de los fármacos , Receptores de Mineralocorticoides/genética , Factores Sexuales , Transducción de Señal , Espironolactona/uso terapéutico , Transcripción Genética , Migración Transendotelial y Transepitelial , Resultado del Tratamiento , Células U937 , Adulto JovenRESUMEN
The epithelial Na+ channel (ENaC) constitutes the rate-limiting step for Na+ absorption in the aldosterone-sensitive distal nephron (ASDN) comprising the late distal convoluted tubule (DCT2), connecting tubule (CNT), and collecting duct (CD). Previously, we demonstrated that ENaC activity in the DCT2/CNT transition zone is constitutively high and independent of aldosterone, in contrast to its aldosterone dependence in the late CNT/initial cortical CD (CCD). The mineralocorticoid receptor (MR) is expressed in the entire ASDN. Its activation by glucocorticoids is prevented through 11ß-hydroxysteroid dehydrogenase 2 (11ß-HSD2) abundantly expressed in the late but probably not early part of the ASDN. We hypothesized that ENaC function in the early part of the ASDN is aldosterone independent but may depend on MR activated by glucocorticoids due to low 11ß-HSD2 abundance. To test this hypothesis, we used doxycycline-inducible nephron-specific MR-deficient [MR knockout (KO)] mice. Whole cell ENaC currents were investigated in isolated nephron fragments from the DCT2/CNT or CNT/CCD transition zones using the patch-clamp technique. ENaC activity was detectable in the CNT/CCD of control mice but absent or barely detectable in the majority of CNT/CCD preparations from MR KO mice. Importantly, ENaC currents in the DCT2/CNT were greatly reduced in MR KO mice compared with ENaC currents in the DCT2/CNT of control mice. Immunofluorescence for 11ß-HSD2 was abundant in the CCD, less prominent in the CNT, and very low in the DCT2. We conclude that MR is critically important for maintaining aldosterone-independent ENaC activity in the DCT2/CNT. Aldosterone-independent MR activation is probably mediated by glucocorticoids due to low expression of 11ß-HSD2.NEW & NOTEWORTHY Using a mouse model with inducible nephron-specific mineralocorticoid receptor (MR) deficiency, we demonstrated that MR is not only critical for maintaining aldosterone-dependent ENaC activity in CNT/CCD but also for aldosterone-independent ENaC activity in DCT2/CNT. Furthermore, we demonstrated that cells of this latter nephron segment express little 11ß-HSD2, which probably allows glucocorticoids to stimulate MR, resulting in aldosterone-independent ENaC activity in DCT2/CNT. This site-specific ENaC regulation has physiologically relevant implications for renal sodium and potassium homeostasis.
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Aldosterona/farmacocinética , Túbulos Renales Colectores/metabolismo , Potasio/metabolismo , Receptores de Mineralocorticoides/efectos de los fármacos , Receptores de Mineralocorticoides/metabolismo , Aldosterona/metabolismo , Animales , Canales Epiteliales de Sodio/metabolismo , Ratones , Nefronas/metabolismo , Sodio/metabolismo , Sodio en la Dieta/metabolismoRESUMEN
BACKGROUND: Mineralocorticoid receptors (MR) are highly expressed in limbic brain areas and prefrontal cortex, which are closely related to selective attention to emotional stimuli and emotion recognition. Patients with major depressive disorder (MDD) show alterations in MR functioning and both cognitive processes. MR stimulation improves cognitive processes in MDD and leads to glutamate release that binds upon N-methyl-D-aspartate receptors (NMDA-R). AIMS: We examined (1) whether MR stimulation has beneficial effects on selective attention to emotional stimuli and on emotion recognition and (2) whether these advantageous effects can be improved by simultaneous NMDA-R stimulation. METHODS: We examined 116 MDD patients and 116 healthy controls matched for age (M = 34 years), sex (78% women), and education in the following conditions: no pharmacological stimulation (placebo), MR stimulation (0.4 mg fludrocortisone + placebo), NMDA-R stimulation (placebo + 250 mg D-cycloserine (DCS)), MR + NMDA-R stimulation (fludrocortisone + DCS). An emotional dot probe task and a facial emotion recognition task were used to measure selective attention to emotional stimuli and emotion recognition. RESULTS: Patients with MDD and healthy individuals did not differ in task performance. MR stimulation had no effect on both cognitive processes in both groups. Across groups, NMDA-R stimulation had no effect on selective attention but showed a small effect on emotion recognition by increasing accuracy to recognize angry faces. CONCLUSIONS: Relatively young unmedicated MDD patients showed no depression-related cognitive deficits compared with healthy controls. Separate MR and simultaneous MR and NMDA-R stimulation revealed no advantageous effects on cognition, but NMDA-R might be involved in emotion recognition.
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Cognición/fisiología , Trastorno Depresivo Mayor/fisiopatología , Receptores de Mineralocorticoides/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Adulto , Estudios de Casos y Controles , Cognición/efectos de los fármacos , Cicloserina/farmacología , Emociones/efectos de los fármacos , Emociones/fisiología , Reconocimiento Facial/efectos de los fármacos , Reconocimiento Facial/fisiología , Femenino , Fludrocortisona/farmacología , Humanos , Masculino , Persona de Mediana Edad , Receptores de Mineralocorticoides/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/agonistas , Adulto JovenRESUMEN
Chronic kidney disease contributes to hypertension, but the mechanisms are incompletely understood. To address this, we applied the 5/6th nephrectomy rat model to characterize hypertension and the response to dietary salt and renin-angiotensin inhibition. 5/6th nephrectomy caused low-renin, salt-sensitive hypertension with hyperkalemia and unsuppressed aldosterone. Compared with sham rats, 5/6th nephrectomized rats had lower Na+/H+ exchanger isoform 3, Na+-K+-2Cl- cotransporter, Na+-Cl- cotransporter, α-epithelial Na+ channel (ENaC), and Kir4.1 levels but higher serum and glucocorticoid-regulated kinase 1, prostasin, γ-ENaC, and Kir5.1 levels. These differences correlated with plasma renin, aldosterone, and/or K+. On a normal-salt diet, adrenalectomy (0 ± 9 mmHg) and spironolactone (-11 ± 10 mmHg) prevented a progressive rise in blood pressure (10 ± 8 mmHg), and this was enhanced in combination with losartan (-41 ± 12 and -43 ± 9 mmHg). A high-salt diet caused skin Na+ and water accumulation and aggravated hypertension that could only be attenuated by spironolactone (-16 ± 7 mmHg) and in which the additive effect of losartan was lost. Spironolactone also increased natriuresis, reduced skin water accumulation, and restored vasorelaxation. In summary, in the 5/6th nephrectomy rat chronic kidney disease model, salt-sensitive hypertension develops with a selective increase in γ-ENaC and despite appropriate transporter adaptations to low renin and hyperkalemia. With a normal-salt diet, hypertension in 5/6th nephrectomy depends on angiotensin II and aldosterone, whereas a high-salt diet causes more severe hypertension mediated through the mineralocorticoid receptor.NEW & NOTEWORTHY Chronic kidney disease (CKD) causes salt-sensitive hypertension, but the interactions between dietary salt and the renin-angiotensin system are incompletely understood. In rats with CKD on a normal-salt diet targeting aldosterone, the mineralocorticoid receptor (MR) and especially angiotensin II reduced blood pressure. On a high-salt diet, however, only MR blockade attenuated hypertension. These results reiterate the importance of dietary salt restriction to maintain renin-angiotensin system inhibitor efficacy and specify the MR as a target in CKD.
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Presión Sanguínea/efectos de los fármacos , Insuficiencia Renal Crónica/tratamiento farmacológico , Sistema Renina-Angiotensina/efectos de los fármacos , Renina/farmacología , Cloruro de Sodio Dietético/toxicidad , Aldosterona/sangre , Angiotensina II/farmacología , Animales , Antihipertensivos/farmacología , Ratas , Receptores de Mineralocorticoides/efectos de los fármacos , Receptores de Mineralocorticoides/metabolismo , Insuficiencia Renal Crónica/inducido químicamente , Cloruro de Sodio Dietético/metabolismo , Espironolactona/farmacologíaRESUMEN
Aldosterone is a steroid hormone that regulates blood pressure and cardiovascular function by acting on renal and vascular mineralocorticoid receptors (MRs) to promote sodium retention and modulate endothelial function. Indeed, MRs are expressed in endothelial cells, vascular smooth muscle cells, adipocytes, immune cells, skeletal muscle cells, and cardiomyocytes. Excessive aldosterone and associated MR activation impair insulin secretion, insulin metabolic signaling to promote development of diabetes, and the related cardiometabolic syndrome. These adverse effects of aldosterone are mediated, in part, via increased inflammation, oxidative stress, dyslipidemia, and ectopic fat deposition. Therefore, inhibition of MR activation may have a beneficial effect in prevention of impaired insulin metabolic signaling, type 2 diabetes, and cardiometabolic disorders. This review highlights findings from the recent surge in research regarding MR-related cardiometabolic disorders as well as our contemporary understanding of the detrimental effects of excess MR activation on insulin metabolic signaling.
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Aldosterona/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Resistencia a la Insulina , Síndrome Metabólico/metabolismo , Receptores de Mineralocorticoides/metabolismo , Animales , Glucemia/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/fisiopatología , Humanos , Hipoglucemiantes/farmacología , Metabolismo de los Lípidos , Síndrome Metabólico/tratamiento farmacológico , Síndrome Metabólico/fisiopatología , Antagonistas de Receptores de Mineralocorticoides/farmacología , Estrés Oxidativo , Receptores de Mineralocorticoides/efectos de los fármacos , Transducción de SeñalRESUMEN
BACKGROUND: Recently, mineralocorticoid receptors (MR) were identified in peripheral nociceptive neurons, and their acute antagonism was responsible for immediate and short-lasting (non-genomic) antinociceptive effects. The same neurons were shown to produce the endogenous ligand aldosterone by the enzyme aldosterone synthase. METHODS: Here, we investigate whether endogenous aldosterone contributes to inflammation-induced hyperalgesia via the distinct genomic regulation of specific pain signaling molecules in an animal model of Freund's complete adjuvant (FCA)-induced hindpaw inflammation. RESULTS: Chronic intrathecal application of MR antagonist canrenoate-K (over 4 days) attenuated nociceptive behavior in rats with FCA hindpaw inflammation suggesting a tonic activation of neuronal MR by endogenous aldosterone. Consistently, double immunofluorescence confocal microscopy showed abundant co-localization of MR with several pain signaling molecules such as TRPV1, CGRP, Nav1.8, and trkA whose enhanced expression of mRNA and proteins during inflammation was downregulated following i.t. canrenoate-K. More importantly, inhibition of endogenous aldosterone production in peripheral sensory neurons by continuous intrathecal delivery of a specific aldosterone synthase inhibitor prevented the inflammation-induced enhanced transcriptional expression of TRPV1, CGRP, Nav1.8, and trkA and subsequently attenuated nociceptive behavior. Evidence for such a genomic effect of endogenous aldosterone was supported by the demonstration of an enhanced nuclear translocation of MR in peripheral sensory dorsal root ganglia (DRG) neurons. CONCLUSION: Taken together, chronic inhibition of local production of aldosterone by its processing enzyme aldosterone synthase within peripheral sensory neurons may contribute to long-lasting downregulation of specific pain signaling molecules and may, thus, persistently reduce inflammation-induced hyperalgesia.
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Aldosterona/metabolismo , Hiperalgesia/metabolismo , Inflamación/metabolismo , Dolor/metabolismo , Animales , Citocromo P-450 CYP11B2/antagonistas & inhibidores , Masculino , Antagonistas de Receptores de Mineralocorticoides/farmacología , Nociceptores/efectos de los fármacos , Nociceptores/metabolismo , Ratas , Ratas Wistar , Receptores de Mineralocorticoides/efectos de los fármacos , Receptores de Mineralocorticoides/metabolismoRESUMEN
Primary cilia are nonmotile sensory organelles found on the surface of almost all kidney tubule epithelial cells. Being exposed to the tubular lumen, primary cilia are thought to be chemo- and mechanosensors of luminal composition and flux, respectively. We hypothesized that, Na+ transport and primary cilia exist in a sensory functional connection in mature renal tubule epithelial cells. Our results demonstrate that primary cilium length is reduced in mineralocorticoid receptor (MR) knockout (KO) mice in a cell autonomous manner along the aldosterone-sensitive distal nephron (ADSN) compared with wild type (as µm ± SEM; 3.1 ± 0.2 vs 4.0 ± 0.1). In mouse cortical collecting duct (mCCD)cl1 cells, which are a model of collecting duct (CD) principal cells, changes in Na+ transport intensity were found to mediate primary cilium length in response to aldosterone (as µm ± SEM: control: 2.7 ± 0.9 vs aldosterone treated: 3.8 ± 0.8). Cilium length was positively correlated with the availability of IFT88, a major intraflagellar anterograde transport complex B component, which is stabilized in response to exposure to aldosterone treatment. This suggests that the abundance of IFT88 is a regulated, rate limiting factor in the elongation of primary cilia. As previously observed in vivo, aldosterone treatment increased cell volume of cultured CD principal cells. Knockdown of IFT88 prevents ciliogenesis and inhibits the adaptive increase in cell size that was observed in response to aldosterone treatment. In conclusion, our results reveal a functional connection between Na+ transport, primary cilia, and cell size, which may play a key role in the morphological and functional adaptation of the CD to sustained changes in active Na+ reabsorption due to variations in aldosterone secretion.
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Aldosterona/farmacología , Transporte Biológico/efectos de los fármacos , Cilios/efectos de los fármacos , Células Epiteliales/efectos de los fármacos , Túbulos Renales Colectores/efectos de los fármacos , Aldosterona/metabolismo , Animales , Cilios/metabolismo , Células Epiteliales/metabolismo , Riñón/efectos de los fármacos , Riñón/metabolismo , Túbulos Renales Colectores/citología , Ratones , Nefronas/efectos de los fármacos , Receptores de Mineralocorticoides/efectos de los fármacos , Receptores de Mineralocorticoides/metabolismo , Sodio/metabolismoRESUMEN
OBJECTIVE: We aimed to study the association among venlafaxine antidepressive outcome, NR3C2 gene polymorphisms and the change of two neuroendocrine hormones during treatment. METHODS: 195 Chinese Han major depressive disorder (MDD) patients were recruited and received a 6-week venlafaxine treatment in this study. Adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH) levels were measured at the beginning and at the end of treatment. Six single-nucleotide polymorphisms (SNPs) (NR3C2: rs1512325, rs1512342, rs2070951; NR3C1: rs6191, rs6196, rs10482614) were selected for high-throughput SNP genotyping. Allele and genotype frequencies of them were compared between remission and non-remission groups. RESULTS: We found that genotype frequency of the rs1512325 located in the NR3C2 gene was significantly different between remission and non-remission groups respectively (p < 0.05). Meanwhile, the frequency of the rs1512325 C-allele was significantly lower (p < 0.05) in remission group. The TSH concentration significantly increased after venlafaxine treatment in remission group (p < 0.05). CONCLUSION: The rs1512325 in NR3C2 gene and TSH concentration may be related to venlafaxine treatment outcome in Chinese Han MDD patients.
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Antidepresivos/farmacología , Trastorno Depresivo Mayor/tratamiento farmacológico , Trastorno Depresivo Mayor/genética , Receptores de Mineralocorticoides/efectos de los fármacos , Clorhidrato de Venlafaxina/farmacología , Adulto , Alelos , Pueblo Asiatico/genética , Trastorno Depresivo Mayor/sangre , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Variantes Farmacogenómicas , Polimorfismo de Nucleótido Simple , Receptores de Mineralocorticoides/genética , Tirotropina/sangre , Resultado del TratamientoRESUMEN
Endocrine-disrupting chemicals (EDCs) have received significant concern, since they ubiquitously exist in the environment and are able to induce adverse health effects on human and wildlife. Increasing evidence shows that the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR), members of the steroid receptor subfamily, are potential targets for EDCs. GR and MR mediate the actions of glucocorticoids and mineralocorticoids, respectively, which are two main classes of corticosteroids involved in many physiological processes. The effects of EDCs on the homeostasis of these two classes of corticosteroids have also gained more attention recently. This review summarized the effects of environmental GR/MR ligands on receptor activity, and disruption of corticosteroid homeostasis. More than 130 chemicals classified into 7 main categories were reviewed, including metals, metalloids, pesticides, bisphenol analogues, flame retardants, other industrial chemicals and pharmaceuticals. The mechanisms by which EDCs interfere with GR/MR activity are primarily involved in ligand-receptor binding, nuclear translocation of the receptor complex, DNA-receptor binding, and changes in the expression of endogenous GR/MR genes. Besides directly interfering with receptors, enzyme-catalyzed synthesis and prereceptor regulation pathways of corticosteroids are also important targets for EDCs. The collected evidence suggests that corticosteroids and their receptors should be considered as potential targets for safety assessment of EDCs. The recognition of relevant xenobiotics and their underlying mechanisms of action is still a challenge in this emerging field of research.
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Disruptores Endocrinos/farmacología , Contaminantes Ambientales/farmacología , Glucocorticoides/metabolismo , Receptores de Mineralocorticoides/efectos de los fármacos , Animales , Homeostasis/efectos de los fármacos , HumanosRESUMEN
Angiotensin II (AngII) and the mineralocorticoid receptor (MR) ligand aldosterone both contribute to cardiovascular disorders, including hypertension and adverse vascular remodeling. We previously demonstrated that AngII activates MR-mediated gene transcription in human vascular smooth muscle cells (SMCs), yet the mechanism and the impact on SMC function are unknown. Using an MR-responsive element-driven transcriptional reporter assay, we confirm that AngII induces MR transcriptional activity in vascular SMCs and endothelial cells, but not in Cos1 or human embryonic kidney-293 cells. AngII activation of MR was blocked by the MR antagonist spironolactone or eplerenone and the protein kinase C-δ (PKCδ) inhibitor rottlerin, implicating both in the mechanism. Similarly, small interfering RNA knockdown of PKCδ in SMCs prevented AngII-mediated MR activation, whereas knocking down of MR blocked both aldosterone- and AngII-induced MR function. Coimmunoprecipitation studies reveal that endogenous MR and PKCδ form a complex in SMCs that is enhanced by AngII treatment in association with increased serine phosphorylation of the MR N terminus. AngII increased mRNA expression of the SMC-MR target gene, FKBP51, via an MR-responsive element in intron 5 of the FKBP51 gene. The impact of AngII on FKBP51 reporter activity and gene expression in SMCs was inhibited by spironolactone and rottlerin. Finally, the AngII-induced increase in SMC number was also blocked by the MR antagonist spironolactone and the PKCδ inhibitor rottlerin. These data demonstrate that AngII activates MR transcriptional regulatory activity, target gene regulation, and SMC proliferation in a PKCδ-dependent manner. This new mechanism may contribute to synergy between MR and AngII in driving SMC dysfunction and to the cardiovascular benefits of MR and AngII receptor blockade in humans.
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Angiotensina II/farmacología , Miocitos del Músculo Liso/fisiología , Proteína Quinasa C-delta/fisiología , Receptores de Mineralocorticoides/efectos de los fármacos , Proliferación Celular , Células HEK293 , Humanos , Fosforilación , Receptores de Mineralocorticoides/fisiología , Proteínas de Unión a Tacrolimus/genética , Activación Transcripcional/efectos de los fármacosRESUMEN
Psychological stress and excess glucocorticoids are associated with metabolic and cardiovascular diseases. Glucocorticoids act primarily through mineralocorticoid (MR) and glucocorticoid receptors (GR), and compounds modulating these receptors show promise in mitigating metabolic and cardiovascular-related phenotypes. CORT118335 (GR/MR modulator) prevents high-fat diet-induced weight gain and adiposity in mice, but the ability of this compound to reverse obesity-related symptoms is unknown. Adult male rats were subcutaneously administered CORT118335 (3, 10, or 30 mg/kg) or vehicle once daily. A 5-day treatment with CORT118335 at 30 mg/kg induced weight loss in rats fed a chow diet by decreasing food intake. However, lower doses of the compound attenuated body weight gain primarily because of decreased calorific efficiency, as there were no significant differences in food intake compared with vehicle. Notably, the body weight effects of CORT118335 persisted during a 2-wk treatment hiatus, suggesting prolonged effects of the compound. To our knowledge, we are the first to demonstrate a sustained effect of combined GR/MR modulation on body weight gain. These findings suggest that CORT118335 may have long-lasting effects, likely due to GR/MR-induced transcriptional changes. Prolonged (18 days) treatment of CORT118335 (10 mg/kg) reversed body weight gain and adiposity in animals fed a high-fat diet for 13 wk. Surprisingly, this occurred despite a worsening of the lipid profile and glucose homeostasis as well as a disrupted diurnal corticosterone rhythm, suggesting GR agonistic effects in the periphery. We conclude that species and tissue-specific targeting may result in promising leads for exploiting the metabolically beneficial aspects of GR/MR modulation.
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Adiposidad/efectos de los fármacos , Metabolismo Energético/efectos de los fármacos , Metabolismo de los Lípidos/efectos de los fármacos , Antagonistas de Receptores de Mineralocorticoides/farmacología , Receptores de Glucocorticoides/antagonistas & inhibidores , Receptores de Mineralocorticoides/efectos de los fármacos , Timina/análogos & derivados , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/metabolismo , Animales , Glucemia/metabolismo , Dieta Alta en Grasa , Ingestión de Alimentos/efectos de los fármacos , Masculino , Tamaño de los Órganos/efectos de los fármacos , Ratas , Ratas Long-Evans , Ratas Sprague-Dawley , Receptores de Glucocorticoides/metabolismo , Receptores de Mineralocorticoides/metabolismo , Timina/farmacología , Aumento de Peso/efectos de los fármacosRESUMEN
BACKGROUND: The progression of chronic renal failure in patients with unilateral renal injury is associated with loss of function in the contralateral kidney, but the molecular mechanism remains unclear. The activation of mineralocorticoid receptor (MR) in the kidney contributes to renal cell damage, leading to apoptosis, pyroptosis, and necrosis. Pyroptosis is a programmed cell death induced by caspase-1, which is usually activated by nod-like receptor pyrin-containing 3 (NLRP3) inï¬ammasomes. Our study aimed to investigate the effects of eplerenone (EPL) on cell pyroptosis in the contralateral kidneys of unilateral ureteral obstruction (UUO) rats. METHODS: Sprague-Dawley rats were randomly divided into 3 groups: sham group, UUO group (10 days of left ureter ligation), and UUO treated with EPL (UUO + EPL) group. The contralateral kidneys of all rats were collected for studies. RESULTS: We observed evidently increased number of pyroptosis cells in the contralateral kidneys of UUO rats compared to those from Sham rats. The expression of NLRP3, caspase-1, interleukin-1ß, serum and glucocorticoid-inducible protein kinase-1, and nuclear factor kappa B were also upregulated in the contralateral kidneys of UUO rats compared to Sham kidneys, and these effects were reduced by MR blocker EPL. CONCLUSION: Our data suggest that the activation of MR is involved in NLRP3/caspase-1 pathway-induced cell pyroptosis in the contralateral kidney of UUO model.
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Eplerenona/farmacología , Riñón/efectos de los fármacos , Piroptosis/efectos de los fármacos , Obstrucción Ureteral/tratamiento farmacológico , Animales , Caspasa 1/fisiología , Riñón/patología , Masculino , FN-kappa B/fisiología , Proteína con Dominio Pirina 3 de la Familia NLR/fisiología , Ratas , Ratas Sprague-Dawley , Receptores de Mineralocorticoides/efectos de los fármacos , Obstrucción Ureteral/patologíaRESUMEN
Cardiomyopathy is a leading cause of death for Duchenne muscular dystrophy. Here, we find that the mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) can share common ligands but play distinct roles in dystrophic heart and skeletal muscle pathophysiology. Comparisons of their ligand structures indicate that the Δ9,11 modification of the first-in-class drug vamorolone enables it to avoid interaction with a conserved receptor residue (N770/N564), which would otherwise activate transcription factor properties of both receptors. Reporter assays show that vamorolone and eplerenone are MR antagonists, whereas prednisolone is an MR agonist. Macrophages, cardiomyocytes, and CRISPR knockout myoblasts show vamorolone is also a dissociative GR ligand that inhibits inflammation with improved safety over prednisone and GR-specific deflazacort. In mice, hyperaldosteronism activates MR-driven hypertension and kidney phenotypes. We find that genetic dystrophin loss provides a second hit for MR-mediated cardiomyopathy in Duchenne muscular dystrophy model mice, as aldosterone worsens fibrosis, mass and dysfunction phenotypes. Vamorolone successfully prevents MR-activated phenotypes, whereas prednisolone activates negative MR and GR effects. In conclusion, vamorolone targets dual nuclear receptors to treat inflammation and cardiomyopathy with improved safety.
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Antiinflamatorios/uso terapéutico , Cardiomiopatías/tratamiento farmacológico , Antagonistas de Receptores de Mineralocorticoides/uso terapéutico , Miocarditis/tratamiento farmacológico , Pregnadienodioles/uso terapéutico , Receptores de Glucocorticoides/efectos de los fármacos , Receptores de Mineralocorticoides/efectos de los fármacos , Aldosterona/química , Aldosterona/farmacología , Aldosterona/uso terapéutico , Animales , Antiinflamatorios/química , Antiinflamatorios/farmacología , Proteína 9 Asociada a CRISPR/genética , Simulación por Computador , Modelos Animales de Enfermedad , Eplerenona/química , Eplerenona/farmacología , Eplerenona/uso terapéutico , Técnicas de Inactivación de Genes , Enlace de Hidrógeno , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones , Ratones Endogámicos C57BL , Antagonistas de Receptores de Mineralocorticoides/química , Antagonistas de Receptores de Mineralocorticoides/farmacología , Distrofia Muscular de Duchenne/tratamiento farmacológico , Miocarditis/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Prednisolona/química , Prednisolona/farmacología , Prednisolona/uso terapéutico , Pregnadienodioles/química , Pregnadienodioles/farmacología , Células RAW 264.7 , Receptores de Glucocorticoides/química , Receptores de Glucocorticoides/genética , Receptores de Mineralocorticoides/agonistas , Receptores de Mineralocorticoides/químicaRESUMEN
Cypermethrin (CP) is a kind of chiral pesticides that has been defined as endocrine disrupting chemical. The diversity in bioactivity, toxicity, metabolism, bioaccumulation, and degradation behaviors of CP enantiomers as well as the research deficiency had made the risk assessment of CP enantiomers very complicated. Herein, four CP enantiomers were separated as target chemicals to investigate their enantioselective endocrine disrupting effects. Firstly, dual-luciferase reporter gene assays were adopted to investigate their potential endocrine disrupting effects via various receptors. The expression levels of steroid hormones related genes and hormone secretion levels in H295R cell were measured to verify the results. Results from the reporter gene assay showed that 1R-cis-αS-CP (CP11) exhibited glucocorticoid receptor (GR), mineralocorticoid receptor (MR), and thyroid receptor (TR) antagonistic activity with the RIC20 values of 9.22â¯×â¯10-7, 3.33â¯×â¯10-7, and 4.47â¯×â¯10-7â¯M, respectively; 1R-trans-αS-CP (CP21) also showed androgen receptor (AR) agonist activity and estrogen receptor (ER) antagonistic activity with the REC20 and RIC20 values were 1.07â¯×â¯10-4â¯M and 4.78â¯×â¯10-6â¯M, respectively. Results of qRT-PCR and hormone measurement also showed that CP11 and CP21 could disturb the expression of steroid hormones related genes and hormone secretion accordingly. Results provided here can help to understand the enantioselective ecological and health risks of CP enantiomers comprehensively and provide constructive guidance for the safe use of chiral pesticides and the invention of green pesticides.
Asunto(s)
Disruptores Endocrinos/farmacología , Piretrinas/farmacología , Estereoisomerismo , Andrógenos/análisis , Línea Celular , Estrógenos/análisis , Genes Reporteros , Humanos , Plaguicidas/química , Plaguicidas/farmacología , Piretrinas/química , Receptores de Glucocorticoides/efectos de los fármacos , Receptores de Mineralocorticoides/efectos de los fármacosRESUMEN
Glucocorticoids are vital stress response hormones and facilitate stress coping. However, sustained glucocorticoid exposure is associated with negative effects on brain. The precise role of glucocorticoids in depression and anxiety remains unclear. In the present study, we found that rats exposed to chronic unpredictable stress (CUS) showed anxiety-like behavior but not depressive-like behavior in the absence of glucocorticoid production. It was interesting to find that the level of serotonin (5-HT) and the expression of tryptophan hydroxylase-2 (TPH2) were decreased after CUS in the hippocampus in sham rats, while adrenalectomy (ADX) prevented such decreases. In addition, the neurogenesis in hippocampus decreased in both sham and ADX rats after stress exposure. Furthermore, inhibition of mineralocorticoid receptor (MR) with spironolactone induced anxiety like behavior in sham rats but not ADX rats. The proliferation of cells was blocked by spironolactone. In conclusion, our results indicate that MR-dependent neurogenesis was closely related with anxiety-like behavior.
Asunto(s)
Conducta Animal/efectos de los fármacos , Glucocorticoides/farmacología , Receptores de Glucocorticoides/efectos de los fármacos , Receptores de Mineralocorticoides/efectos de los fármacos , Animales , Ansiedad/tratamiento farmacológico , Ansiedad/metabolismo , Depresión/tratamiento farmacológico , Depresión/metabolismo , Glucocorticoides/metabolismo , Masculino , Neurogénesis/efectos de los fármacos , Ratas Sprague-Dawley , Receptores de Glucocorticoides/metabolismo , Receptores de Mineralocorticoides/metabolismo , Serotonina/metabolismo , Estrés Psicológico/tratamiento farmacológico , Estrés Psicológico/metabolismo , Triptófano Hidroxilasa/metabolismoRESUMEN
Activation of the mineralocorticoid receptor (MR) in the distal nephron by its ligand, aldosterone, plays an important role in sodium reabsorption and blood pressure regulation. However, expression of the MR goes beyond the kidney. It is expressed in a variety of other tissues in which its activation could lead to tissue injury. Indeed, MR activation in the cardiovascular (CV) system has been shown to promote hypertension, fibrosis, and inflammation. Pharmacological blockade of the MR has protective effects in several animal models of CV disease. Furthermore, the use of MR antagonists is beneficial for heart failure patients, preventing mortality and morbidity. A better understanding of the implications of the MR in the setting of CV diseases is critical for refining treatments and improving patient care. The mechanisms involved in the deleterious effects of MR activation are complex and include oxidative stress, inflammation, and fibrosis. This review will discuss the pathological role of the MR in the CV system and the major mechanisms underlying it.
Asunto(s)
Enfermedades Cardiovasculares/tratamiento farmacológico , Sistema Cardiovascular/efectos de los fármacos , Antagonistas de Receptores de Mineralocorticoides/uso terapéutico , Receptores de Mineralocorticoides/efectos de los fármacos , Animales , Enfermedades Cardiovasculares/metabolismo , Enfermedades Cardiovasculares/mortalidad , Enfermedades Cardiovasculares/fisiopatología , Sistema Cardiovascular/metabolismo , Sistema Cardiovascular/fisiopatología , Humanos , Antagonistas de Receptores de Mineralocorticoides/efectos adversos , Receptores de Mineralocorticoides/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
Children and adults prenatally exposed to alcohol show higher rates of mental health problems than unexposed individuals, with depression and anxiety being among the more commonly encountered disorders. Previous studies in rats showed that prenatal alcohol exposure (PAE) can indeed increase depressive- and anxiety-like behavior in adulthood; however, depression and anxiety are often observed in the context of stress and/or a dysregulated stress response system (the hypothalamic-pituitary-adrenal [HPA] axis). PAE can dysregulate the HPA axis, resulting in hyperresponsivity to stress. In turn, this may predispose individuals prenatally exposed to alcohol to the adverse effects of stress compared to unexposed individuals. We have shown previously that PAE animals may be more sensitive to the effects of chronic stress on behavior, showing increased anxiety- and depressive-like behavior following chronic unpredictable stress (CUS) exposure. Here, we investigated the independent and interactive effects of PAE and adult CUS on anxiety-like behavior and receptor systems (corticotropin-releasing hormone receptor type 1 [CRHR1], mineralocorticoid receptor [MR], and glucocorticoid receptor [GR]), and underlying stress and emotional regulation, and whether exposure to CUS differentially results in immediate or delayed effects. Adult male and female offspring from PAE, pair-fed (PF), and ad libitum-fed control (C) dams were exposed to either 10 days of CUS or left undisturbed. Behavioral testing began 1 or 14 days post-CUS, and brains were collected following testing. Anxiety-like behaviors were evaluated using the open field, elevated plus maze and dark-light emergence tests. CRHR1, MR, and GR mRNA expression were assessed in the medial prefrontal cortex (mPFC), amygdala, and hippocampal formation, brain areas key to both stress and emotional regulation. We found that PAE differentially increased anxiety-like behavior and altered GR mRNA in males and females compared to their control counterparts. Furthermore, depending on the timing of testing, CUS unmasked alterations in GR and CRHR1 mRNA expression in the mPFC and amygdala in PAE males, and MR mRNA in the hippocampal formation in PAE females compared to their C counterparts. Overall, the changes observed in these receptor systems may underlie the increase in anxiety-like behavior following PAE and CUS exposure in adulthood. That CUS differentially affected brain and behavioral outcome of PAE and C animals, and did so in a sexually-dimorphic manner, has important implications for understanding the etiology of psychopathology in individuals prenatally exposed to alcohol.
Asunto(s)
Etanol/efectos adversos , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Estrés Psicológico/etiología , Animales , Ansiedad/etiología , Ansiedad/metabolismo , Trastornos de Ansiedad/metabolismo , Depresión/etiología , Depresión/metabolismo , Trastorno Depresivo/metabolismo , Etanol/metabolismo , Femenino , Hipocampo , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Masculino , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Corteza Prefrontal , Embarazo , ARN Mensajero , Ratas , Ratas Sprague-Dawley , Receptores de Hormona Liberadora de Corticotropina/análisis , Receptores de Hormona Liberadora de Corticotropina/efectos de los fármacos , Receptores de Glucocorticoides/análisis , Receptores de Glucocorticoides/efectos de los fármacos , Receptores de Mineralocorticoides/análisis , Receptores de Mineralocorticoides/efectos de los fármacos , Factores Sexuales , Estrés Psicológico/fisiopatología , Factores de TiempoRESUMEN
Recent advances in the field of mineralocorticoid receptor (MR) and its ligand aldosterone expanded the role of this hormone and its receptor far beyond their initial function as a regulator of Na+ and K+ homeostasis in epithelial cells. The symposium "New Roles of Aldosterone and Mineralocorticoid Receptors in Cardiovascular Disease: Translational and Sex-Specific Effects" presented at the 38th World Congress of the International Union of Physiological Sciences (Rio de Janeiro, Brazil) highlighted the contribution of extrarenal MRs to cardiovascular disease. This symposium showcased how MRs expressed in endothelial, vascular smooth muscle, and immune cells plays a critical role in the development of vascular disease associated with aging, obesity, and chronic aldosterone stimulation and demonstrated that MR antagonism prevents the acute renal dysfunction and tubular injury induced by ischemia-reperfusion injury. It was also shown that the adipocyte-derived hormone leptin is a new direct regulator of aldosterone secretion and that leptin-mediated aldosterone production is a major contributor to obesity-associated hypertension in women. Sex differences in the role of aldosterone and of endothelial MR in the cardiovascular outcomes of obesity were highlighted. This review summarizes these important emerging concepts regarding the contribution of aldosterone and cell-specific MR to cardiovascular disease in male and female subjects and further supports sex-specific benefits of MR antagonist drugs to be tested in additional populations.
Asunto(s)
Aldosterona/metabolismo , Enfermedades Cardiovasculares/metabolismo , Sistema Cardiovascular/metabolismo , Riñón/metabolismo , Receptores de Mineralocorticoides/metabolismo , Investigación Biomédica Traslacional , Factores de Edad , Animales , Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedades Cardiovasculares/inmunología , Enfermedades Cardiovasculares/fisiopatología , Sistema Cardiovascular/efectos de los fármacos , Sistema Cardiovascular/inmunología , Sistema Cardiovascular/fisiopatología , Congresos como Asunto , Femenino , Humanos , Riñón/efectos de los fármacos , Riñón/fisiopatología , Ligandos , Masculino , Antagonistas de Receptores de Mineralocorticoides/uso terapéutico , Receptores de Mineralocorticoides/efectos de los fármacos , Factores Sexuales , Transducción de SeñalRESUMEN
Acute kidney injury induced by ischemia/reperfusion is an independent risk factor for chronic kidney disease. Macrophage recruitment plays an essential role during the injury and repair phases after an ischemic episode in the kidney. Here we show that the novel non-steroidal mineralocorticoid receptor antagonist finerenone or selective myeloid mineralocorticoid receptor ablation protects against subsequent chronic dysfunction and fibrosis induced by an episode of bilateral kidney ischemia/reperfusion in mice. This protection was associated with increased expression of M2-antiinflamatory markers in macrophages from finerenone-treated or myeloid mineralocorticoid receptor-deficient mice. Moreover, the inflammatory population of CD11b+, F4/80+, Ly6Chigh macrophages was also reduced. Mineralocorticoid receptor inhibition promoted increased IL-4 receptor expression and activation in the whole kidney and in isolated macrophages, thereby facilitating macrophage polarization to an M2 phenotype. The long-term protection conferred by mineralocorticoid receptor antagonism was also translated to the Large White pig pre-clinical model. Thus, our studies support the rationale for using mineralocorticoid receptor antagonists in clinical practice to prevent transition of acute kidney injury to chronic kidney disease.