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Cardiovascular Endocrinology &... Sep 2023This review examines the role of mineralocorticoid receptor antagonists (MRAs) in cardiovascular biology and the molecular mechanisms involved in mineralocorticoid... (Review)
Review
This review examines the role of mineralocorticoid receptor antagonists (MRAs) in cardiovascular biology and the molecular mechanisms involved in mineralocorticoid receptor antagonism. The data discussed suggest that MRAs can play an important role in decreasing the impact of inflammation and fibrosis on cardiorenal outcomes. Evidence derived from major randomized clinical trials demonstrates that steroidal MRAs reduce mortality in patients with heart failure and reduced ejection fraction. Initial positive findings observed in patients with chronic kidney disease and type 2 diabetes (T2D) indicate the possible mechanisms of action of nonsteroidal MRAs, and the clinical benefits for patients with cardiorenal disease and T2D. This article supports the application of basic science concepts to expand our understanding of the molecular mechanisms of action involved in pathophysiology. This approach encourages the development of treatment options before diseases clinically manifest. Video Abstract: http://links.lww.com/CAEN/A42.
PubMed: 37614245
DOI: 10.1097/XCE.0000000000000289 -
Diabetologia Feb 2024The overactivation of the mineralocorticoid receptor (MR) promotes pathophysiological processes related to multiple physiological systems, including the heart,... (Review)
Review
The overactivation of the mineralocorticoid receptor (MR) promotes pathophysiological processes related to multiple physiological systems, including the heart, vasculature, adipose tissue and kidneys. The inhibition of the MR with classical MR antagonists (MRA) has successfully improved outcomes most evidently in heart failure. However, real and perceived risk of side effects and limited tolerability associated with classical MRA have represented barriers to implementing MRA in settings where they have been already proven efficacious (heart failure with reduced ejection fraction) and studying their potential role in settings where they might be beneficial but where risk of safety events is perceived to be higher (renal disease). Novel non-steroidal MRA have distinct properties that might translate into favourable clinical effects and better safety profiles as compared with MRA currently used in clinical practice. Randomised trials have shown benefits of non-steroidal MRA in a range of clinical contexts, including diabetic kidney disease, hypertension and heart failure. This review provides an overview of the literature on the systemic impact of MR overactivation across organ systems. Moreover, we summarise the evidence from preclinical studies and clinical trials that have set the stage for a potential new paradigm of MR antagonism.
Topics: Humans; Diabetic Nephropathies; Heart Failure; Mineralocorticoid Receptor Antagonists; Mineralocorticoids; Naphthyridines; Receptors, Mineralocorticoid
PubMed: 38127122
DOI: 10.1007/s00125-023-06031-1 -
The Journal of Endocrinology Aug 2023Myelination allows fast and synchronized nerve influxes and is provided by Schwann cells (SCs) in the peripheral nervous system. Glucocorticoid hormones are major...
Myelination allows fast and synchronized nerve influxes and is provided by Schwann cells (SCs) in the peripheral nervous system. Glucocorticoid hormones are major regulators of stress, metabolism and immunity affecting all tissues. They act by binding to two receptors, the low-affinity glucocorticoid receptor (GR) and the high-affinity mineralocorticoid receptor (MR). Little is known about the effect of glucocorticoid hormones on the PNS, and this study focuses on deciphering the role of MR in peripheral myelination. In this work, the presence of a functional MR in SCs is demonstrated and the expression of MR protein in mouse sciatic nerve SC is evidenced. Besides, knockout of MR in SC (SCMRKO using Cre-lox system with DesertHedgeHog (Dhh) Cre promoter) was undertaken in mice. SCMRKO was not associated with alterations of performance in motor behavioral tests on 2- to 6-month-old male mice compared to their controls. No obvious modifications of myelin gene expression or MR signaling gene expression were observed in the SCMRKO sciatic nerves. Nevertheless, Gr transcript and GR protein amounts were significantly increased in SCMRKO nerves compared to controls, suggesting a possible compensatory effect. Besides, an increase in myelin sheath thickness was noted for axons with perimeters larger than 15 µm in SCMRKO illustrated by a significant 4.5% reduction in g-ratio (axon perimeter/myelin sheath perimeter). Thus, we defined MR as a new player in peripheral system myelination and in SC homeostasis.
Topics: Male; Mice; Animals; Myelin Sheath; Receptors, Mineralocorticoid; Glucocorticoids; Mice, Knockout; Schwann Cells; Sciatic Nerve
PubMed: 37195271
DOI: 10.1530/JOE-22-0334 -
Annual Review of Physiology Feb 2024Originally described as the renal aldosterone receptor that regulates sodium homeostasis, it is now clear that mineralocorticoid receptors (MRs) are widely expressed,... (Review)
Review
Originally described as the renal aldosterone receptor that regulates sodium homeostasis, it is now clear that mineralocorticoid receptors (MRs) are widely expressed, including in vascular endothelial and smooth muscle cells. Ample data demonstrate that endothelial and smooth muscle cell MRs contribute to cardiovascular disease in response to risk factors (aging, obesity, hypertension, atherosclerosis) by inducing vasoconstriction, vascular remodeling, inflammation, and oxidative stress. Extrapolating from its role in disease, evidence supports beneficial roles of vascular MRs in the context of hypotension by promoting inflammation, wound healing, and vasoconstriction to enhance survival from bleeding or sepsis. Advances in understanding how vascular MRs become activated are also reviewed, describing transcriptional, ligand-dependent, and ligand-independent mechanisms. By synthesizing evidence describing how vascular MRs convert cardiovascular risk factors into disease (the vascular MR as a foe), we postulate that the teleological role of the MR is to coordinate responses to hypotension (the MR as a friend).
Topics: Humans; Receptors, Mineralocorticoid; Ligands; Endothelium, Vascular; Inflammation; Hypotension
PubMed: 37788489
DOI: 10.1146/annurev-physiol-042022-015223 -
Journal of Clinical Medicine Sep 2023Nonsteroidal mineralocorticoid receptor antagonists (MRAs) present a promising therapeutic option in cardiorenal diseases, mitigating the limitations of steroidal MRAs.... (Review)
Review
Nonsteroidal mineralocorticoid receptor antagonists (MRAs) present a promising therapeutic option in cardiorenal diseases, mitigating the limitations of steroidal MRAs. Finerenone, a third-generation nonsteroidal MRA, has demonstrated beneficial effects in heart failure (HF) and chronic kidney disease (CKD). Clinical trials, including FIDELIO-DKD and FIGARO-DKD, revealed finerenone's efficacy in improving kidney and cardiovascular (CV) outcomes. Patients with CKD and type 2 diabetes (T2DM) on finerenone experienced reduced rates of cardiovascular events, including hospitalization for HF. However, these trials excluded symptomatic HF patients, focusing on asymptomatic or early-stage HF. The ongoing FINEARTS-HF trial evaluates finerenone in HF with preserved ejection fraction (HFpEF). Additionally, studies exploring finerenone and sodium-glucose cotransporter 2 (SGLT2) inhibitors' (Empagliflozin) combination effects in CKD and T2DM (CONFIDENCE) and the selective MR modulator AZD9977 with another SGLT2 inhibitor (dapagliflozin) in HF and CKD (MIRACLE) aim to expand treatment options. While SGLT-2 inhibitors were shown to reduce hyperkalemia risk in FIDELIO-DKD and potentially lower new-onset HF incidence in FIGARO-DKD, further research is essential. So far, the evidence for the beneficial effect of finerenone in the spectrum of cardiorenal diseases is based only on the results of studies conducted in patients with T2DM, and clinical trials of finerenone in patients with nondiabetic kidney disease are ongoing. Nonsteroidal MRAs hold significant potential as pivotal treatment targets across the cardiorenal disease spectrum. This review will focus on the effects of finerenone on cardiorenal disease.
PubMed: 37834929
DOI: 10.3390/jcm12196285 -
Frontiers in Endocrinology 2023Diabetic kidney disease (DKD) is a serious complication of diabetes that can lead to end-stage kidney disease. Despite its significant impact, most research has... (Review)
Review
Diabetic kidney disease (DKD) is a serious complication of diabetes that can lead to end-stage kidney disease. Despite its significant impact, most research has concentrated on the glomerulus, with little attention paid to the tubulointerstitial region, which accounts for the majority of the kidney volume. DKD's tubulointerstitial lesions are characterized by inflammation, fibrosis, and loss of kidney function, and recent studies indicate that these lesions may occur earlier than glomerular lesions. Evidence has shown that inflammatory mechanisms in the tubulointerstitium play a critical role in the development and progression of these lesions. Apart from the renin-angiotensin-aldosterone blockade, Sodium-Glucose Linked Transporter-2(SGLT-2) inhibitors and new types of mineralocorticoid receptor antagonists have emerged as effective ways to treat DKD. Moreover, researchers have proposed potential targeted therapies, such as inhibiting pro-inflammatory cytokines and modulating T cells and macrophages, among others. These therapies have demonstrated promising results in preclinical studies and clinical trials, suggesting their potential to treat DKD-induced tubulointerstitial lesions effectively. Understanding the immune-inflammatory mechanisms underlying DKD-induced tubulointerstitial lesions and developing targeted therapies could significantly improve the treatment and management of DKD. This review summarizes the latest advances in this field, highlighting the importance of focusing on tubulointerstitial inflammation mechanisms to improve DKD outcomes.
Topics: Humans; Diabetic Nephropathies; Inflammation; Kidney Failure, Chronic; Mineralocorticoid Receptor Antagonists; Fibrosis; Diabetes Mellitus
PubMed: 37859992
DOI: 10.3389/fendo.2023.1232790 -
Journal of Endocrinological... Oct 2023The hypothalamic-pituitary-adrenal (HPA) axis exerts many actions on the central nervous system (CNS) aside from stress regulation. Glucocorticoids (GCs) play an... (Review)
Review
PURPOSE
The hypothalamic-pituitary-adrenal (HPA) axis exerts many actions on the central nervous system (CNS) aside from stress regulation. Glucocorticoids (GCs) play an important role in affecting several cognitive functions through the effects on both glucocorticoid (GR) and mineralocorticoid receptors (MR). In this review, we aim to unravel the spectrum of cognitive dysfunction secondary to derangement of circulating levels of endogenous and exogenous glucocorticoids.
METHODS
All relevant human prospective and retrospective studies published up to 2022 in PubMed reporting information on HPA disorders, GCs, and cognition were included.
RESULTS
Cognitive impairment is commonly found in GC-related disorders. The main brain areas affected are the hippocampus and pre-frontal cortex, with memory being the most affected domain. Disease duration, circadian rhythm disruption, circulating GCs levels, and unbalanced MR/GR activation are all risk factors for cognitive decline in these patients, albeit with conflicting data among different conditions. Lack of normalization of cognitive dysfunction after treatment is potentially attributable to GC-dependent structural brain alterations, which can persist even after long-term remission.
CONCLUSION
The recognition of cognitive deficits in patients with GC-related disorders is challenging, often delayed, or mistaken. Prompt recognition and treatment of underlying disease may be important to avoid a long-lasting impact on GC-sensitive areas of the brain. However, the resolution of hormonal imbalance is not always followed by complete recovery, suggesting irreversible adverse effects on the CNS, for which there are no specific treatments. Further studies are needed to find the mechanisms involved, which may eventually be targeted for treatment strategies.
Topics: Humans; Glucocorticoids; Retrospective Studies; Prospective Studies; Hypothalamo-Hypophyseal System; Cognition
PubMed: 37058223
DOI: 10.1007/s40618-023-02091-7 -
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