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Acta Neuropathologica Nov 2023Central serous chorioretinopathy (CSCR) belongs to the pachychoroid spectrum, a pathological phenotype of the choroidal vasculature, in which blood flow is under the...
Central serous chorioretinopathy (CSCR) belongs to the pachychoroid spectrum, a pathological phenotype of the choroidal vasculature, in which blood flow is under the choroidal nervous system (ChNS) regulation. The pathogenesis of CSCR is multifactorial, with the most recognised risk factor being intake of glucocorticoids, which activate both the gluco- and the mineralocorticoid (MR) receptors. As MR over-activation is pathogenic in the retina and choroid, it could mediate the pathogenic effects of glucocorticoids in CSCR. But the role of MR signalling in pachychoroid is unknown and whether it affects the ChNS has not been explored. Using anatomo-neurochemical characterisation of the ChNS in rodents and humans, we discovered that beside innervation of arteries, choroidal veins and choriocapillaris are also innervated, suggesting that the entire choroidal vasculature is under neural control. The numerous synapses together with calcitonin gene-related peptide (CGRP) vesicles juxtaposed to choroidal macrophages indicate a neuro-immune crosstalk. Using ultrastructural approaches, we show that transgenic mice overexpressing human MR, display a pachychoroid-like phenotype, with signs of choroidal neuropathy including myelin abnormalities, accumulation and enlargement of mitochondria and nerves vacuolization. Transcriptomic analysis of the RPE/choroid complex in the transgenic mice reveals regulation of corticoids target genes, known to intervene in nerve pathophysiology, such as Lcn2, rdas1/dexras1, S100a8 and S100a9, rabphilin 3a (Rph3a), secretogranin (Scg2) and Kinesin Family Member 5A (Kif5a). Genes belonging to pathways related to vasculature development, hypoxia, epithelial cell apoptosis, epithelial mesenchymal transition, and inflammation, support the pachychoroid phenotype and highlight downstream molecular targets. Hypotheses on the imaging phenotype of pachychoroid in humans are put forward in the light of these new data. Our results provide evidence that MR overactivation causes a choroidal neuropathy that could explain the pachychoroid phenotype found in transgenic mice overexpressing human MR. In patients with pachychoroid and CSCR in which systemic dysautonomia has been demonstrated, MR-induced choroidal neuropathy could be the missing link between corticoids and pachychoroid.
Topics: Animals; Mice; Humans; Receptors, Mineralocorticoid; Tomography, Optical Coherence; Choroid; Adrenal Cortex Hormones; Glucocorticoids; Nervous System; Mice, Transgenic; Retrospective Studies
PubMed: 37682293
DOI: 10.1007/s00401-023-02628-3 -
Frontiers in Endocrinology 2023Aldosterone, as a mineralocorticoid of adrenal origin, has effects that are not limited to the urinary tract. As an important regulator in Vasoactive hormone pathways,... (Review)
Review
Aldosterone, as a mineralocorticoid of adrenal origin, has effects that are not limited to the urinary tract. As an important regulator in Vasoactive hormone pathways, aldosterone may play an effect in the pathogenesis of diabetic retinopathy (DR) through the regulation of oxidative stress, vascular regulation, and inflammatory mechanisms. This implies that mineralocorticoids, including aldosterone, have great potential and value for the diagnosis and treatment of DR. Because early studies did not focus on the intrinsic association between mineralocorticoids and DR, targeted research is still in its infancy and there are still many obstacles to its application in the clinical setting. Recent studies have improved the understanding of the effects of aldosterone on DR, and we review them with the aim of exploring possible mechanisms for the treatment and prevention of DR.
Topics: Humans; Aldosterone; Mineralocorticoids; Diabetic Retinopathy; Mineralocorticoid Receptor Antagonists; Diabetes Mellitus
PubMed: 37113483
DOI: 10.3389/fendo.2023.1163787 -
Endocrinology Jun 2023Consumption of a Western diet (WD) consisting of excess fat and carbohydrates activates the renin-angiotensin-aldosterone system, which has emerged as an important risk...
Consumption of a Western diet (WD) consisting of excess fat and carbohydrates activates the renin-angiotensin-aldosterone system, which has emerged as an important risk factor for systemic and tissue insulin resistance. We recently discovered that activated mineralocorticoid receptors (MRs) in diet-induced obesity induce CD36 expression, increase ectopic lipid accumulation, and result in systemic and tissue insulin resistance. Here, we have further investigated whether endothelial cell (EC)-specific MR (ECMR) activation participates in WD-induced ectopic skeletal muscle lipid accumulation, insulin resistance, and dysfunction. Six-week-old female ECMR knockout (ECMR-/-) and wild-type (ECMR+/+) mice were fed either a WD or a chow diet for 16 weeks. ECMR-/- mice were found to have decreased WD-induced in vivo glucose intolerance and insulin resistance at 16 weeks. Improved insulin sensitivity was accompanied by increased glucose transporter type 4 expression in conjunction with improved soleus insulin metabolic signaling in phosphoinositide 3-kinases/protein kinase B and endothelial nitric oxide synthase activation. Additionally, ECMR-/- also blunted WD-induced increases in CD36 expression and associated elevations in soleus free fatty acid, total intramyocellular lipid content, oxidative stress, and soleus fibrosis. Moreover, in vitro and in vivo activation of ECMR increased EC-derived exosomal CD36 that was further taken up by skeletal muscle cells, leading to increased skeletal muscle CD36 levels. These findings indicate that in the context of an obesogenic WD, enhanced ECMR signaling increases EC-derived exosomal CD36 resulting in increased uptake and elevated concentrations of CD36 in skeletal muscle cells, contributing to increased lipid metabolic disorders and soleus insulin resistance.
Topics: Mice; Animals; Female; Diet, Western; Insulin Resistance; Receptors, Mineralocorticoid; Muscle, Skeletal; Insulin; Lipids
PubMed: 37289042
DOI: 10.1210/endocr/bqad091 -
Environment International Dec 2019Endocrine-disrupting chemicals (EDCs) have received significant concern, since they ubiquitously exist in the environment and are able to induce adverse health effects... (Review)
Review
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.
Topics: Animals; Endocrine Disruptors; Environmental Pollutants; Glucocorticoids; Homeostasis; Humans; Receptors, Mineralocorticoid
PubMed: 31520960
DOI: 10.1016/j.envint.2019.105133 -
Journal of Translational Medicine Nov 2022Apparent mineralocorticoid excess is an autosomal recessive form of monogenic disease characterized by juvenile resistant low-renin hypertension, marked hypokalemic... (Review)
Review
Apparent mineralocorticoid excess is an autosomal recessive form of monogenic disease characterized by juvenile resistant low-renin hypertension, marked hypokalemic alkalosis, low aldosterone levels, and high ratios of cortisol to cortisone metabolites. It is caused by defects in the HSD11B2 gene, encoding the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), which is primarily involved in the peripheral conversion of cortisol to cortisone. To date, over 50 deleterious HSD11B2 mutations have been identified worldwide. Multiple molecular mechanisms function in the lowering of 11β-HSD2 activity, including damaging protein stability, lowered affinity for the substrate and cofactor, and disrupting the dimer interface. Genetic polymorphism, environmental factors as well as epigenetic modifications may also offer an implicit explanation for the molecular pathogenesis of AME. A precise diagnosis depends on genetic testing, which allows for early and specific management to avoid the morbidity and mortality from target organ damage. In this review, we provide insights into the molecular genetics of classic and non-classic apparent mineralocorticoid excess and aim to offer a comprehensive overview of this monogenic disease.
Topics: Humans; Cortisone; 11-beta-Hydroxysteroid Dehydrogenase Type 2; Hydrocortisone; Hypertension; Molecular Biology; Mineralocorticoid Excess Syndrome, Apparent
PubMed: 36329487
DOI: 10.1186/s12967-022-03698-9 -
Basic Research in Cardiology Apr 2024Inflammaging, a pro-inflammatory status that characterizes aging and primarily involving macrophages, is a master driver of age-related diseases. Mineralocorticoid...
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 TIMD4MHC-II macrophage population by TIMD4MHC-II and TIMD4MHC-II macrophages in the aging heart. By integrating cell sorting and transwell experiments with TIMD4/TIMD4macrophages and fibroblasts from old MR/MR 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.
Topics: Animals; Female; Male; Mice; Fibrosis; Inflammation; Macrophages; Myocardium; Receptors, Mineralocorticoid
PubMed: 38329499
DOI: 10.1007/s00395-024-01032-6 -
American Journal of Nephrology 2023Diabetic kidney disease (DKD) is a common disorder with multiple serious clinical implications, including an increased risk of end-stage kidney disease (ESKD),... (Review)
Review
BACKGROUND
Diabetic kidney disease (DKD) is a common disorder with multiple serious clinical implications, including an increased risk of end-stage kidney disease (ESKD), cardiovascular complications, heart failure, onset or worsening of hypertension, and premature death. Patients with DKD frequently require dialysis or kidney transplantation to manage their ESKD.
SUMMARY
Upregulation of the renin-angiotensin-aldosterone system is an important contributor to kidney disease progression, as highlighted by the results of trials evaluating angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in patients with albuminuria. Increasing evidence suggests the existence of a multidirectional network that involves aldosterone, the mineralocorticoid receptor (MR), and the Ras-related C3 botulinum toxin substrate 1 (Rac1) as driving forces in the generation of reactive oxygen species and oxidative stress-induced injury in the initiation of interstitial nephritis and eventual fibrosis in chronic kidney disease and DKD. The MR is a key element of this triangle, as highlighted by the beneficial effect of MR antagonists in preventing or reducing aldosterone- or Rac1-related effects in basic science studies, and the improved patient outcomes observed in clinical studies.
KEY MESSAGES
Aldosterone can promote kidney disease in diabetes via the MR and via MR-independent actions through Rac1. However, the MR remains a key element of this triangle, with clinical data supporting the use of MR antagonists in delaying the progression of kidney disease in diabetes.
Topics: Humans; Mineralocorticoid Receptor Antagonists; Diabetic Nephropathies; Aldosterone; Receptors, Mineralocorticoid; Clinical Relevance; Kidney Failure, Chronic; Angiotensin Receptor Antagonists; Diabetes Mellitus
PubMed: 36682353
DOI: 10.1159/000528783 -
Current Opinion in Nephrology and... Jul 2022The aim of this study was to present recent developments in pharmacotherapy of hypertension in patients with advanced chronic kidney disease (CKD). (Review)
Review
PURPOSE OF REVIEW
The aim of this study was to present recent developments in pharmacotherapy of hypertension in patients with advanced chronic kidney disease (CKD).
RECENT FINDINGS
In the AMBER trial, compared with placebo, the potassium-binder patiromer mitigated the risk of hyperkalaemia and enabled more patients with uncontrolled resistant hypertension and stage 3b/4 CKD to tolerate and continue spironolactone treatment; add-on therapy with spironolactone provoked a clinically meaningful reduction of 11-12 mmHg in unattended automated office SBP over 12 weeks of follow-up. In the BLOCK-CKD trial, the investigational nonsteroidal mineralocorticoid-receptor-antagonist (MRA) KBP-5074 lowered office SBP by 7-10 mmHg relative to placebo at 84 days with a minimal risk of hyperkalaemia in patients with advanced CKD and uncontrolled hypertension. The CLICK trial showed that the thiazide-like diuretic chlorthalidone provoked a placebo-subtracted reduction of 10.5 mmHg in 24-h ambulatory SBP at 12 weeks in patients with stage 4 CKD and poorly controlled hypertension.
SUMMARY
Enablement of more persistent spironolactone use with newer potassium-binding agents, the clinical development of novel nonsteroidal MRAs with a more favourable benefit-risk profile and the recently proven blood pressure lowering action of chlorthalidone are three therapeutic opportunities for more effective management of hypertension in high-risk patients with advanced CKD.
Topics: Blood Pressure; Chlorthalidone; Humans; Hyperkalemia; Hypertension; Mineralocorticoid Receptor Antagonists; Piperidines; Potassium; Pyrazoles; Quinolines; Renal Insufficiency, Chronic; Spironolactone
PubMed: 35727171
DOI: 10.1097/MNH.0000000000000812 -
International Journal of Molecular... Apr 2023Stress is known to have a significant impact on mental health. While gender differences can be found in stress response and mental disorders, there are limited studies... (Review)
Review
Stress is known to have a significant impact on mental health. While gender differences can be found in stress response and mental disorders, there are limited studies on the neuronal mechanisms of gender differences in mental health. Here, we discuss gender and cortisol in depression as presented by recent clinical studies, as well as gender differences in the role of glucocorticoid receptors (GRs) and mineralocorticoid receptors (MRs) in stress-associated mental disorders. When examining clinical studies drawn from PubMed/MEDLINE (National Library of Medicine) and EMBASE, salivary cortisol generally showed no gender correlation. However, young males were reported to show heightened cortisol reactivity compared to females of similar age in depression. Pubertal hormones, age, early life stressors, and types of bio-samples for cortisol measurement affected the recorded cortisol levels. The role of GRs and MRs in the HPA axis could be different between males and females during depression, with increased HPA activity and upregulated MR expression in male mice, while the inverse happened in female mice. The functional heterogeneity and imbalance of GRs and MRs in the brain may explain gender differences in mental disorders. This knowledge and understanding will support the development of gender-specific diagnostic markers involving GRs and MRs in depression.
Topics: Male; Female; Mice; Animals; Hydrocortisone; Receptors, Glucocorticoid; Hypothalamo-Hypophyseal System; Sex Factors; Depression; Pituitary-Adrenal System; Receptors, Mineralocorticoid; Stress, Psychological
PubMed: 37108291
DOI: 10.3390/ijms24087129