RÉSUMÉ
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.
Sujet(s)
Évolution moléculaire , Gorilla gorilla , Pan troglodytes , Récepteurs des minéralocorticoïdes , Animaux , Récepteurs des minéralocorticoïdes/génétique , Récepteurs des minéralocorticoïdes/métabolisme , Humains , Pan troglodytes/génétique , Gorilla gorilla/génétique , Phylogenèse , Pongo/génétique , Séquence d'acides aminés , Domaines protéiquesRÉSUMÉ
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 11ß-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: 0.45â¯nM and 0.30â¯nM) and maximal response (31- and 23-fold increase from baseline) on hMR; 18oxoF and 18OHB displayed lower potency (19.6â¯nM and 56.0â¯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 20â¯nM (CV1-MRLuc) to â¼2000â¯nM, while the EC50 for aldosterone remained unchanged. The addition of 18ß-glycyrrhetinic acid (18ß-GA), a HSD11B2 inhibitor, restored the potency of cortisol back to â¼70â¯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.
Sujet(s)
11-beta-Hydroxysteroid dehydrogenase type 2 , Aldostérone , Antagonistes des récepteurs des minéralocorticoïdes , Récepteurs des minéralocorticoïdes , Récepteurs des minéralocorticoïdes/métabolisme , Récepteurs des minéralocorticoïdes/génétique , Récepteurs des minéralocorticoïdes/agonistes , Humains , 11-beta-Hydroxysteroid dehydrogenase type 2/métabolisme , 11-beta-Hydroxysteroid dehydrogenase type 2/génétique , 11-beta-Hydroxysteroid dehydrogenase type 2/antagonistes et inhibiteurs , Aldostérone/métabolisme , Antagonistes des récepteurs des minéralocorticoïdes/pharmacologie , Animaux , Hydrocortisone/métabolisme , Hydrocortisone/pharmacologie , Lignée cellulaireRÉSUMÉ
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.
Sujet(s)
Axe hypothalamohypophysaire , Axe hypophyso-surrénalien , État prédiabétique , Animaux , Femelle , Mâle , Grossesse , Rats , Hormone corticotrope/sang , Hormone corticotrope/métabolisme , Corticostérone/sang , Corticostérone/métabolisme , Diabète de type 2/métabolisme , Axe hypothalamohypophysaire/métabolisme , Insulinorésistance , Axe hypophyso-surrénalien/métabolisme , État prédiabétique/métabolisme , Effets différés de l'exposition prénatale à des facteurs de risque/métabolisme , Rat Sprague-Dawley , Récepteurs aux glucocorticoïdes/métabolisme , Récepteurs aux glucocorticoïdes/génétique , Récepteurs des minéralocorticoïdes/métabolisme , Récepteurs des minéralocorticoïdes/génétiqueRÉSUMÉ
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.
Sujet(s)
Tumeurs , Récepteurs des minéralocorticoïdes , Humains , Récepteurs des minéralocorticoïdes/métabolisme , Récepteurs des minéralocorticoïdes/génétique , Tumeurs/métabolisme , Tumeurs/génétique , Animaux , Régulation de l'expression des gènes tumorauxRÉSUMÉ
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.
Sujet(s)
Ischémie , Leptine , Placenta , Pré-éclampsie , Récepteurs des minéralocorticoïdes , Animaux , Grossesse , Femelle , Leptine/métabolisme , Leptine/sang , Placenta/métabolisme , Placenta/vascularisation , Ischémie/physiopathologie , Ischémie/métabolisme , Ischémie/génétique , Récepteurs des minéralocorticoïdes/métabolisme , Récepteurs des minéralocorticoïdes/génétique , Pré-éclampsie/métabolisme , Pré-éclampsie/physiopathologie , Pré-éclampsie/génétique , Souris knockout , Pression sanguine , Souris de lignée C57BL , Souris , Modèles animaux de maladie humaine , Retard de croissance intra-utérin/métabolisme , Retard de croissance intra-utérin/physiopathologie , Retard de croissance intra-utérin/génétique , Endothélium vasculaire/métabolisme , Endothélium vasculaire/physiopathologie , Vasodilatation/effets des médicaments et des substances chimiquesRÉSUMÉ
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 50â¯% 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.
Sujet(s)
Aldostérone , Récepteurs des minéralocorticoïdes , Activation de la transcription , Humains , Récepteurs des minéralocorticoïdes/génétique , Récepteurs des minéralocorticoïdes/métabolisme , Aldostérone/pharmacologie , Aldostérone/métabolisme , Activation de la transcription/effets des médicaments et des substances chimiques , Cellules HEK293 , Sérine/métabolisme , Sérine/génétique , Lysine/métabolisme , Lysine/composition chimique , Tryptophane/métabolisme , Domaines protéiques , Cystéine/métabolisme , ADN/métabolisme , ADN/génétiqueRÉSUMÉ
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.
Sujet(s)
Aldostérone , Glucuronidase , Protéines Klotho , Souris knockout , Potassium , Protéines Klotho/métabolisme , Animaux , Humains , Souris , Potassium/métabolisme , Aldostérone/métabolisme , Glucuronidase/métabolisme , Glucuronidase/génétique , Mâle , Néphrons/métabolisme , Potassium alimentaire/métabolisme , Potassium alimentaire/administration et posologie , Femelle , Récepteurs des minéralocorticoïdes/métabolisme , Récepteurs des minéralocorticoïdes/génétique , Souris de lignée C57BLSujet(s)
Rein , Antagonistes des récepteurs des minéralocorticoïdes , Humains , Antagonistes des récepteurs des minéralocorticoïdes/usage thérapeutique , Animaux , Récepteurs des minéralocorticoïdes/métabolisme , Récepteurs des minéralocorticoïdes/génétique , Minéralocorticoïdes/métabolisme , Aldostérone/métabolismeRÉSUMÉ
Endothelial cells play crucial roles in physiology and are increasingly recognized as therapeutic targets in cardiovascular disease. Here, we analyzed the regulatory landscape of cardiac endothelial cells by assessing chromatin accessibility, histone modifications, and 3D chromatin organization and confirmed the functional relevance of enhancer-promoter interactions by CRISPRi-mediated enhancer silencing. We used this dataset to explore mechanisms of transcriptional regulation in cardiovascular disease and compared six different experimental models of heart failure, hypertension, or diabetes. Enhancers that regulate gene expression in diseased endothelial cells were enriched with binding sites for a distinct set of transcription factors, including the mineralocorticoid receptor (MR), a known drug target in heart failure and hypertension. For proof of concept, we applied endothelial cell-specific MR deletion in mice to confirm MR-dependent gene expression and predicted direct MR target genes. Overall, we have compiled here a comprehensive atlas of cardiac endothelial cell enhancer elements that provides insight into the role of transcription factors in cardiovascular disease.
Sujet(s)
Ascomycota , Maladies cardiovasculaires , Défaillance cardiaque , Hypertension artérielle , Animaux , Souris , Cellules endothéliales , Récepteurs des minéralocorticoïdes/génétique , Facteurs de transcription , Éléments activateurs (génétique) , Expression des gènesRÉSUMÉ
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 ß 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.
Sujet(s)
Hypertension artérielle , Myosin-light-chain phosphatase , Animaux , Souris , Aldostérone/pharmacologie , Aldostérone/métabolisme , Fibrose , Hypertension artérielle/génétique , Hypertension artérielle/métabolisme , Myocytes cardiaques/métabolisme , Myosin-light-chain phosphatase/génétique , Myosin-light-chain phosphatase/métabolisme , Phosphorylation , Récepteurs des minéralocorticoïdes/génétique , Récepteurs des minéralocorticoïdes/métabolismeRÉSUMÉ
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-IIneg/low macrophage population by TIMD4+MHC-IIint/high and TIMD4-MHC-IIint/high macrophages in the aging heart. By integrating cell sorting and transwell experiments with TIMD4+/TIMD4-macrophages and fibroblasts from old MRflox/MRLysMCre 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.
Sujet(s)
Myocarde , Récepteurs des minéralocorticoïdes , Animaux , Femelle , Mâle , Souris , Fibrose , Inflammation/métabolisme , Macrophages/métabolisme , Myocarde/anatomopathologie , Récepteurs des minéralocorticoïdes/génétique , Récepteurs des minéralocorticoïdes/métabolismeRÉSUMÉ
The mineralocorticoid receptor (MR) is a transcription factor for genes mediating diverse, cell-specific functions, including trophic effects as well as promoting fluid/electrolyte homeostasis. It was reported that in intercalated cells, phosphorylation of the MR at serine 843 (S843) by Unc-51-like kinase (ULK1) inhibits MR activation and that phosphorylation of ULK1 by mechanistic target of rapamycin (mTOR) inactivates ULK1, and thereby prevents MR inactivation. We extended these findings with studies in M1 mouse cortical collecting duct cells stably expressing the rat MR and a reporter gene. Pharmacological inhibition of ULK1 dose-dependently increased ligand-induced MR transactivation, while ULK1 activation had no effect. Pharmacological inhibition of mTOR and CRISPR/gRNA gene knockdown of rapamycin-sensitive adapter protein of mTOR (Raptor) or rapamycin-insensitive companion of mTOR (Rictor) decreased phosphorylated ULK1 and ligand-induced activation of the MR reporter gene, as well as transcription of endogenous MR-target genes. As predicted, ULK1 inhibition had no effect on aldosterone-mediated transcription in M1 cells with the mutated MR-S843A (alanine cannot be phosphorylated). In contrast, mTOR inhibition dose-dependently decreased transcription in the MR-S843A cells, though not as completely as in cells with the wild-type MR-S843. mTOR, Raptor, and Rictor coprecipitated with the MR and addition of aldosterone increased their phosphorylated, active state. These results suggest that mTOR significantly regulates MR activity in at least 2 ways: by suppressing MR inactivation by ULK1, and by a yet ill-defined mechanism that involves direct association with MR. They also provide new insights into the diverse functions of ULK1 and mTOR, 2 key enzymes that monitor the cell's energy status.
Sujet(s)
Aldostérone , Récepteurs des minéralocorticoïdes , Animaux , Souris , Rats , Homologue de la protéine-1 associée à l'autophagie/génétique , Homologue de la protéine-1 associée à l'autophagie/métabolisme , Ligands , Complexe-1 cible mécanistique de la rapamycine/métabolisme , Complexes multiprotéiques/métabolisme , Phosphorylation , Compagnon de mTOR insensible à la rapamycine/métabolisme , Récepteurs des minéralocorticoïdes/génétique , Récepteurs des minéralocorticoïdes/métabolisme , Protéine de régulation associée à mTOR , , Sirolimus/pharmacologie , Sérine-thréonine kinases TOR/métabolisme , Facteurs de transcription/métabolismeRÉSUMÉ
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.
Sujet(s)
Colite , Maladies inflammatoires intestinales , Souris , Animaux , Récepteurs des minéralocorticoïdes/génétique , Récepteurs des minéralocorticoïdes/métabolisme , Aldostérone/métabolisme , Éplérénone , Minéralocorticoïdes/métabolisme , Immunité innée , Espèces réactives de l'oxygène/métabolisme , Lymphocytes , Colite/induit chimiquement , Colite/traitement médicamenteux , Inflammation/métabolismeRÉSUMÉ
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.
Sujet(s)
Méthylation de l'ADN , Axe hypothalamohypophysaire , Moineaux , Axe hypothalamohypophysaire/métabolisme , Méthylation de l'ADN/génétique , Axe hypophyso-surrénalien/métabolisme , Récepteurs aux glucocorticoïdes/génétique , Récepteurs aux glucocorticoïdes/métabolisme , Stress physiologique/génétique , Récepteurs des minéralocorticoïdes/génétique , Récepteurs des minéralocorticoïdes/métabolismeRÉSUMÉ
Aldosterone (Aldo) exerts its action through binding with the mineralocorticoid receptor (MR). Clinically, a link between primary aldosteronism (PA) and thyroid diseases has been hypothesised. However, the presence and activity of MR on the thyroid have not yet been demonstrated. We investigated the gene/protein expression and activation of MR in primary thyroid cell cultures (normal rat thyroid [FRTL-5] and human papillary thyroid cancer [PTC] cell lines, BCPAP and K1) through qRT-PCR analysis, immunofluorescence, and confocal microscopy. We also studied the effects of Aldo on thyroid-specific and inflammation genes in vitro. Paired human normal and neoplastic thyroid tissues were also studied. We demonstrated both gene and protein expression and activation of MR in normal rat thyroid and human PTC lines. Incubation with Aldo induced an acute increase in IL-6 expression in both the FRTL-5 and BCPAP lines, which was antagonised by spironolactone, and an acute and late upregulation of thyroid-specific genes in FRTL-5. MR was also expressed at both gene and protein levels in normal human thyroid tissues and in PTC, with a progressive decline during neoplastic tumourigenesis, particularly in more aggressive histotypes. We present the first evidence of MR gene and protein expression in both normal and pathological thyroid cells and tissues. We have shown that MR is present and functionally activated in thyroid tissue. Binding of Aldo to MR induces the expression of inflammatory and thyroid-specific genes, and the thyroid may thus be considered a novel mineralocorticoid target tissue.
Sujet(s)
Récepteurs des minéralocorticoïdes , Tumeurs de la thyroïde , Animaux , Humains , Rats , Aldostérone/pharmacologie , Techniques de culture cellulaire , Minéralocorticoïdes , Récepteurs des minéralocorticoïdes/génétique , Cancer papillaire de la thyroïdeRÉSUMÉ
Diabetic Kidney Disease (DKD) is a significant complication of diabetes and primary cause of end-stage renal disease globally. The exact mechanisms underlying DKD remain poorly understood, but multiple factors, including the renin-angiotensin-aldosterone system (RAAS), play a key role in its progression. Aldosterone, a mineralocorticoid steroid hormone, is one of the key components of RAAS and a potential mediator of renal damage and inflammation in DKD. miRNAs, small noncoding RNA molecules, have attracted interest due to their regulatory roles in numerous biological processes. These processes include aldosterone signaling and mineralocorticoid receptor (MR) expression. Numerous miRNAs have been recognized as crucial regulators of aldosterone signaling and MR expression. These miRNAs affect different aspects of the RAAS pathway and subsequent molecular processes, which impact sodium balance, ion transport, and fibrosis regulation. This review investigates the regulatory roles of particular miRNAs in modulating aldosterone signaling and MR activation, focusing on their impact on kidney injury, inflammation, and fibrosis. Understanding the complex interaction between miRNAs and the RAAS could lead to a new strategy to target aldosterone signaling and MR activation using miRNAs. This highlights the potential of miRNA-based interventions for DKD, with the aim of enhancing kidney outcomes in individuals with diabetes.
Sujet(s)
Néphropathies diabétiques , microARN , Humains , Aldostérone , Néphropathies diabétiques/génétique , Fibrose , Inflammation , microARN/génétique , Minéralocorticoïdes , Récepteurs des minéralocorticoïdes/génétiqueRÉSUMÉ
Stressors in the environment of aquatic organisms can profoundly affect their immune system. The stress response in fish involves the activation of the hypothalamus-pituitary-interrenal (HPI) axis, leading to the release of several stress hormones, among them glucocorticoids, such as cortisol, which bind and activate corticosteroid receptors, namely the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR). These receptors are highly expressed on immune cells, thereby allowing stress to have a potent effect that is classically considered to suppress immune function. In this review, we highlight the conserved structure and function of GR and MR among vertebrates and describe their role in modulating inflammation by regulating the expression of pro-inflammatory and anti-inflammatory genes. In particular, the involvement of MR during inflammation is reviewed, which in many studies has been shown to be immune-enhancing. In recent years, the use of zebrafish as a model organism has opened up new possibilities to study the effects of stress on inflammation, making it possible to investigate knockout lines for MR and/or GR, in combination with transgenic models with fluorescently labeled leukocyte subpopulations that enable the visualization and manipulation of these immune cells. The potential roles of other hormones of the HPI axis, such as corticotrophin-releasing hormone (Crh) and adrenocorticotropic hormone (Acth), in immune modulation are also discussed. Overall, this review highlights the need for further research to elucidate the specific roles of GR, MR and other stress hormones in regulating immune function in fish. Understanding these mechanisms will contribute to improving fish health and advancing our knowledge of stress signalling.
Sujet(s)
Récepteurs aux stéroïdes , Danio zébré , Animaux , Danio zébré/métabolisme , Récepteurs des minéralocorticoïdes/génétique , Récepteurs des minéralocorticoïdes/métabolisme , Récepteurs aux stéroïdes/métabolisme , Récepteurs aux glucocorticoïdes/génétique , Récepteurs aux glucocorticoïdes/métabolisme , Glucocorticoïdes/métabolisme , Inflammation , Axe hypothalamohypophysaire/métabolismeRÉSUMÉ
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.
Sujet(s)
Hormones corticosurrénaliennes , Récepteurs des minéralocorticoïdes , Récepteurs des minéralocorticoïdes/génétique , Récepteurs des minéralocorticoïdes/métabolisme , Ligands , Récepteurs aux glucocorticoïdes/génétique , Récepteurs aux glucocorticoïdes/métabolisme , ADN/métabolisme , Récepteurs cytoplasmiques et nucléairesRÉSUMÉ
Objectives: To investigate the current situation regarding occupational burnout among coal miners, explore the relationship between NR3C2 gene polymorphism and occupational burnout, and analyze the influence of the interaction between environment and gene on occupational burnout. This study provides a scientific basis for formulating health strategies to combat job burnout. Methods: A total of 1,500 first-line coal mine workers were selected by cluster random sampling, and the job burnout scale, job content questionnaire (JCQ), and simplified coping style questionnaire (SCSQ) were used for the questionnaire survey. A total of 150 workers were randomly selected from the high burnout group and the low burnout group, and a total of 300 workers were selected as the research objects to examine the relationship between gene polymorphism, environment-gene interactions and burnout. This study employed iMLDRTM genotyping technology for NR3C2 gene (rs5522, rs2070950) polymorphism analysis. The relationship between the occurrence of job burnout, occupational stress, coping styles and the NR3C2 gene was analyzed. Results: Finally, a total of 1,282 valid questionnaires were retrieved, with an effective recovery rate of 85.5%. The study included 128 participants (10%) with zero burnout, 400 (31.2%) with mild burnout, 649 (50.6%) with moderate burnout and 105 (8.2%) with severe burnout. There were significant differences in the rate of burnout among miners with respect to sex, age, working years, educational level, shifts, and marital status (P < 0.05). The difference in occupational stress between the different job burnout groups was statistically significant (P < 0.05). Compared with the GG genotype of rs2070950 of the NR3C2 gene, the CC genotype was identified as a susceptibility gene for occupational burnout (P < 0.05). In respect to rs5522, rs2070950, occupational stress, positive coping, and negative coping, the low-risk group was unlikely to suffer from job burnout compared with the high-risk group (OR = 0.103, 95%CI: 0.058-0.182). Conclusion: In addition to demographic characteristics, occupational stress and negative coping styles were also identified as risk factors for job burnout. The interaction between locus rs5522, locus rs2070950, occupational stress, positive response, and negative response were found to affect the incidence of occupational burnout.
Sujet(s)
Épuisement professionnel , Mineurs (métier) , Stress professionnel , Polymorphisme génétique , Humains , Adaptation psychologique , Épuisement professionnel/épidémiologie , Charbon , Stress professionnel/épidémiologie , Récepteurs des minéralocorticoïdes/génétiqueRÉSUMÉ
Preclinical and human studies suggest a role of aldosterone and mineralocorticoid receptor (MR) in addiction. This scoping review aimed to summarize (1) the relationship between alcohol and other substance use disorders (ASUDs) and dysfunctions of the aldosterone and MR, and (2) how pharmacological manipulations of MR may affect ASUD-related outcomes. Our search in four databases (MEDLINE, Embase, Web of Science, and Cochrane Library) indicated that most studies focused on the relationship between aldosterone, MR, and alcohol (n = 30), with the rest focused on opioids (n = 5), nicotine (n = 9), and other addictive substances (n = 9). Despite some inconsistencies, the overall results suggest peripheral and central dysregulations of aldosterone and MR in several species and that these dysregulations depended on the pattern of drug exposure and genetic factors. We conclude that MR antagonism may be a promising target in ASUD, yet future studies are warranted.