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New Paradigms in Aldosterone and Mineralocorticoid Receptor Pathophysiology

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 January 2023) | Viewed by 26028

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Special Issue Editors

Dr. Frédéric Jaisser

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Guest Editor

Centre de Recherche des Cordeliers, Sorbonne Université, Université de Paris, Paris, France
Interests: hypertension; cardiorenal; chronic kidney disease; mineralocorticoid; cardiovascular diseases

Prof. Dr. Diego Alvarez de la Rosa

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Co-Guest Editor

Department of Basic Medical Sciences, Institute of Biomedical Technologies and Center for Biomedical Research of the Canary Islands, Universidad de La Laguna, San Cristóbal de La Laguna, Spain
Interests: aldosterone; mineralocorticoid receptor; epithelial sodium channel; sgk1

Dr. Jonatan Barrera-Chimal

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Co-Guest Editor

Maisonneuve Rosemont Hospital Research Center, Montreal, QC, Canada
Interests: medicine, biochemistry, genetics and molecular biology; mitral valve prolapse; heart failure

Special Issue Information

Dear Colleagues,

A paradigm shift occurred in our understanding of the pathophysiological roles of aldosterone, a steroid hormone, and its main receptor, the mineralocorticoid receptor (MR). Such advances include 1) the better understanding of the regulation of aldosterone synthesis and its implication in primary aldosteronism; 2) the description of alternative aldosterone receptors such as the G protein-coupled estrogen receptor (GPER; 3) the identification of the broader than previously recognized cell/tissue expression of the mineralocorticoid receptor, with major implications from cardiovascular diseases to diabetic and non-diabetic renal disease progression, metabolic diseases or eye, skin, liver diseases for example; 4) the identification of novel signaling pathways including cellular energetics, inflammation and immune modulation; 5) the development of aldosterone synthase inhibitors and novel MR antagonists (MRAs), like non-steroidal MRAs with improved therapeutic index with limited hyperkalemia risk, opening the way to a broader and safer use of MR antagonists.

This Special Issue will publish original research articles as well as full reviews on the current understanding of molecular mechanisms involved in aldosterone and mineralocorticoid receptor pathophysiology. Manuscripts on the novel cellular and molecular mechanisms modulated by aldosterone and activation of the mineralocorticoid receptor and their implication at the cell, tissue and organ levels are welcome, as well as reports on the pathophysiological roles of aldosterone/MR on organ crosstalk, comorbidities and chronic disease progression leading to the potential use of aldosterone and MR antagonists. Manuscripts based on clinical studies will not be considered.

Dr. Frédéric Jaisser
Prof. Dr. Diego Alvarez de la Rosa
Dr. Jonatan Barrera-Chimal
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

mineralocorticoid
cardiovascular
kidney
inflammation
diabetes

Published Papers (10 papers)

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Research

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15 pages, 1965 KiB

Open AccessArticle

Neutral Effect of Skeletal Muscle Mineralocorticoid Receptor on Glucose Metabolism in Mice

by Alessandra Feraco, Stefania Gorini, Caterina Mammi, Mauro Lombardo, Andrea Armani and Massimiliano Caprio

Int. J. Mol. Sci. 2023, 24(8), 7412; https://doi.org/10.3390/ijms24087412 - 18 Apr 2023

Viewed by 1088

Abstract

The mineralocorticoid receptor (MR) is able to regulate the transcription of a number of genes in the myotube, although its roles in skeletal muscle (SM) metabolism still await demonstration. SM represents a major site for glucose uptake, and its metabolic derangements play a pivotal role in the development of insulin resistance (IR). The aim of this study was to investigate the contribution of SM MR in mediating derangements of glucose metabolism in a mouse model of diet-induced obesity. We observed that mice fed a high-fat diet (HFD mice) showed impaired glucose tolerance compared to mice fed a normal diet (ND mice). Mice fed a 60% HFD treated with the MR antagonist Spironolactone (HFD + Spiro) for 12 weeks revealed an improvement in glucose tolerance, as measured with an intraperitoneal glucose tolerance test, compared with HFD mice. To investigate if blockade of SM MR could contribute to the favorable metabolic effects observed with pharmacological MR antagonism, we analyzed MR expression in the gastrocnemius, showing that SM MR protein abundance is downregulated by HFD compared to ND mice and that pharmacological treatment with Spiro was able to partially revert this effect in HFD + Spiro mice. Differently from what we have observed in adipose tissue, where HDF increased adipocyte MR expression, SM MR protein was down-regulated in our experimental model, suggesting a completely different role of SM MR in the regulation of glucose metabolism. To confirm this hypothesis, we investigated the effects of MR blockade on insulin signaling in a cellular model of IRin C2C12 myocytes, which were treated with or without Spiro. We confirmed MR protein downregulation in insulin-resistant myotubes. We also analyzed Akt phosphorylation upon insulin stimulation, and we did not observe any difference between palmitate- and palmitate + Spiro-treated cells. These results were confirmed by in vitro glucose uptake analysis. Taken together, our data indicate that reduced activity of SM MR does not improve insulin signaling in mouse skeletal myocytes and does not contribute to the favorable metabolic effects on glucose tolerance and IR induced by systemic pharmacological MR blockade. Full article

(This article belongs to the Special Issue New Paradigms in Aldosterone and Mineralocorticoid Receptor Pathophysiology)

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14 pages, 1976 KiB

Open AccessArticle

Benefits of the Non-Steroidal Mineralocorticoid Receptor Antagonist Finerenone in Metabolic Syndrome-Related Heart Failure with Preserved Ejection Fraction

by Ixchel Lima-Posada, Yohan Stephan, Matthieu Soulié, Roberto Palacios-Ramirez, Benjamin Bonnard, Lionel Nicol, Peter Kolkhof, Frederic Jaisser and Paul Mulder

Int. J. Mol. Sci. 2023, 24(3), 2536; https://doi.org/10.3390/ijms24032536 - 28 Jan 2023

Cited by 3 | Viewed by 2621

Abstract

The mineralocorticoid receptor (MR) plays an important role in the development of chronic kidney disease (CKD) and associated cardiovascular complications. Antagonizing the overactivation of the MR with MR antagonists (MRA) is a therapeutic option, but their use in patients with CKD is limited due to the associated risk of hyperkalemia. Finerenone is a non-steroidal MRA associated with an improved benefit-risk profile in comparison to steroidal MRAs. In this study, we decided to test whether finerenone improves renal and cardiac function in male hypertensive and diabetic ZSF1 rats as an established preclinical HFpEF model. Finerenone was administered at 10 mg/kg/day for 12 weeks. Cardiac function/hemodynamics were assessed in vivo. ZSF1 rats showed classical signs of CKD with increased BUN, UACR, hypertrophy, and fibrosis of the kidney together with characteristic signs of HFpEF including cardiac fibrosis, diastolic dysfunction, and decreased cardiac perfusion. Finerenone treatment did not impact kidney function but reduced renal hypertrophy and cardiac fibrosis. Interestingly, finerenone ameliorated diastolic dysfunction and cardiac perfusion in ZSF1 rats. In summary, we show for the first time that non-steroidal MR antagonism by finerenone attenuates cardiac diastolic dysfunction and improves cardiac perfusion in a preclinical HFpEF model. These cardiac benefits were found to be largely independent of renal benefits. Full article

(This article belongs to the Special Issue New Paradigms in Aldosterone and Mineralocorticoid Receptor Pathophysiology)

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21 pages, 4912 KiB

Open AccessArticle

Novel 1,4-Dihydropyridine Derivatives as Mineralocorticoid Receptor Antagonists

by Felipe Luis Pérez-Gordillo, Natalia Serrano-Morillas, Luz Marina Acosta-García, María Teresa Aranda, Daniela Passeri, Roberto Pellicciari, María Jesús Pérez de Vega, Rosario González-Muñiz, Diego Alvarez de la Rosa and Mercedes Martín-Martínez

Int. J. Mol. Sci. 2023, 24(3), 2439; https://doi.org/10.3390/ijms24032439 - 26 Jan 2023

Cited by 1 | Viewed by 1778

Abstract

The mineralocorticoid receptor (MR) belongs to the steroid receptor subfamily of nuclear receptors. MR is a transcription factor key in regulating blood pressure and mineral homeostasis. In addition, it plays an important role in a broad range of biological and pathological conditions, greatly expanding its interest as a pharmacological target. Non-steroidal MR antagonists (MRAs) are of particular interest to avoid side effects and achieve tissue-specific modulation of the receptor. The 1,4-dihydropyridine (1,4-DHP) ring has been identified as an appropriate scaffold to develop non-steroidal MRAs. We report the identification of a novel series of 1,4-DHP that has been guided by structure-based drug design, focusing on the less explored DHP position 2. Interestingly, substituents at this position might interfere with MR helix H12 disposition, which is essential for the recruitment of co-regulators. Several of the newly synthesized 1,4-DHPs show interesting properties as MRAs and have a good selectivity profile. These 1,4-DHPs promote MR nuclear translocation with less efficiency than the natural agonist aldosterone, which explains, at least in part, its antagonist character. Molecular dynamic studies are suggestive of several derivatives interfering with the disposition of H12 in the agonist-associated conformation, and thus, they might stabilize an MR conformation unable to recruit co-activators. Full article

(This article belongs to the Special Issue New Paradigms in Aldosterone and Mineralocorticoid Receptor Pathophysiology)

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16 pages, 29149 KiB

Open AccessArticle

Finerenone, a Non-Steroidal Mineralocorticoid Receptor Antagonist, Reduces Vascular Injury and Increases Regulatory T-Cells: Studies in Rodents with Diabetic and Neovascular Retinopathy

by Jack R. Jerome, Devy Deliyanti, Varaporn Suphapimol, Peter Kolkhof and Jennifer L. Wilkinson-Berka

Int. J. Mol. Sci. 2023, 24(3), 2334; https://doi.org/10.3390/ijms24032334 - 25 Jan 2023

Cited by 5 | Viewed by 3108

Abstract

Vision loss in diabetic retinopathy features damage to the blood–retinal barrier and neovascularization, with hypertension and the renin–angiotensin system (RAS) having causal roles. We evaluated if finerenone, a non-steroidal mineralocorticoid receptor (MR) antagonist, reduced vascular pathology and inflammation in diabetic and neovascular retinopathy. Diabetic and hypertensive transgenic (mRen-2)27 rats overexpressing the RAS received the MR antagonist finerenone (10 mg/kg/day, oral gavage) or the angiotensin-converting enzyme inhibitor perindopril (10 mg/kg/day, drinking water) for 12 weeks. As retinal neovascularization does not develop in diabetic rodents, finerenone (5 mg/kg/day, i.p.) was evaluated in murine oxygen-induced retinopathy (OIR). Retinal vasculopathy was assessed by measuring gliosis, vascular leakage, neovascularization, and VEGF. Inflammation was investigated by quantitating retinal microglia/macrophages, pro-inflammatory mediators, and anti-inflammatory regulatory T-cells (Tregs). In diabetes, both treatments reduced systolic blood pressure, gliosis, vascular leakage, and microglial/macrophage density, but only finerenone lowered VEGF, ICAM-1, and IL-1ß. In OIR, finerenone reduced neovascularization, vascular leakage, and microglial density, and increased Tregs in the blood, spleen, and retina. Our findings, in the context of the FIDELIO-DKD and FIGARO-DKD trials reporting the benefits of finerenone on renal and cardiovascular outcomes in diabetic kidney disease, indicate the potential of finerenone as an effective oral treatment for diabetic retinopathy. Full article

(This article belongs to the Special Issue New Paradigms in Aldosterone and Mineralocorticoid Receptor Pathophysiology)

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14 pages, 1730 KiB

Open AccessArticle

Effects of Chronic Kidney Disease on Nanomechanics of the Endothelial Glycocalyx Are Mediated by the Mineralocorticoid Receptor

by Benedikt Fels, Arne Beyer, Violeta Cazaña-Pérez, Teresa Giraldez, Juan F. Navarro-González, Diego Alvarez de la Rosa, Franz Schaefer, Aysun K. Bayazit, Łukasz Obrycki, Bruno Ranchin, Johannes Holle, Uwe Querfeld and Kristina Kusche-Vihrog

Int. J. Mol. Sci. 2022, 23(18), 10659; https://doi.org/10.3390/ijms231810659 - 13 Sep 2022

Cited by 2 | Viewed by 1558

Abstract

Endothelial mechanics control vascular reactivity and are regulated by the mineralocorticoid receptor (MR) and its downstream target, the epithelial Na⁺ channel (ENaC). Endothelial dysfunction is a hallmark of chronic kidney disease (CKD), but its mechanisms are poorly understood. We hypothesized that CKD disrupts endothelial mechanics in an MR/ENaC-dependent process. Methods: Primary human endothelial cells were cultured with uremic serum derived from children with stage 3–5 (predialysis) CKD or adult hemodialysis (HD) patients or healthy controls. The height and stiffness of the endothelial glycocalyx (eGC) and cortex were monitored by atomic force microscopy (AFM) using an ultrasensitive mechanical nanosensor. Results: In a stage-dependent manner, sera from children with CKD induced a significant increase in eGC and cortex stiffness and an incremental reduction of the eGC height. AFM measurements were significantly associated with individual pulse wave velocity and serum concentrations of gut-derived uremic toxins. Serum from HD patients increased MR expression and mechanical stiffness of the endothelial cortex, an effect reversed by MR and ENaC antagonists, decreased eNOS expression and NO bioavailability, and augmented monocyte adhesion. Conclusion: These data indicate progressive structural damage of the endothelial surface with diminishing kidney function and identify the MR as a mediator of CKD-induced endothelial dysfunction. Full article

(This article belongs to the Special Issue New Paradigms in Aldosterone and Mineralocorticoid Receptor Pathophysiology)

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15 pages, 4385 KiB

Open AccessArticle

Biglycan Is a Novel Mineralocorticoid Receptor Target Involved in Aldosterone/Salt-Induced Glomerular Injury

by Toshifumi Nakamura, Benjamin Bonnard, Roberto Palacios-Ramirez, Amaya Fernández-Celis, Frédéric Jaisser and Natalia López-Andrés

Int. J. Mol. Sci. 2022, 23(12), 6680; https://doi.org/10.3390/ijms23126680 - 15 Jun 2022

Cited by 1 | Viewed by 1798

Abstract

The beneficial effects of mineralocorticoid receptor (MR) antagonists (MRAs) for various kidney diseases are established. However, the underlying mechanisms of kidney injury induced by MR activation remain to be elucidated. We recently reported aldosterone-induced enhancement of proteoglycan expression in mitral valve interstitial cells and its association with fibromyxomatous valvular disorder. As the expression of certain proteoglycans is elevated in several kidney diseases, we hypothesized that proteoglycans mediate kidney injury in the context of aldosterone/MR pathway activation. We evaluated the proteoglycan expression and tissue injury in the kidney and isolated glomeruli of uninephrectomy/aldosterone/salt (NAS) mice. The MRA eplerenone was administered to assess the role of the MR pathway. We investigated the direct effects of biglycan, one of the proteoglycans, on macrophages using isolated macrophages. The kidney samples from NAS-treated mice showed enhanced fibrosis and increased expression of biglycan accompanying glomerular macrophage infiltration and enhanced expression of TNF-α, iNOS, Nox2, CCL3 (C-C motif chemokine ligand 3), and phosphorylated NF-κB. Eplerenone blunted these changes. Purified biglycan stimulated macrophages to express TNF-α, iNOS, Nox2, and CCL3. This was prevented by a toll-like receptor 4 (TLR4) or NF-κB inhibitor, indicating that biglycan stimulation is dependent on the TLR4/NF-κB pathway. We identified the proteoglycan biglycan as a novel target of MR involved in MR-induced glomerular injury and macrophage infiltration via a biglycan/TLR4/NF-κB/CCL3 cascade. Full article

(This article belongs to the Special Issue New Paradigms in Aldosterone and Mineralocorticoid Receptor Pathophysiology)

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Review

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8 pages, 233 KiB

Open AccessReview

Spontaneous Remission of Primary Aldosteronism with Mineralocorticoid Receptor Antagonist Therapy: A Review

by Xurong Mai, Mitsuhiro Kometani and Takashi Yoneda

Int. J. Mol. Sci. 2022, 23(22), 13821; https://doi.org/10.3390/ijms232213821 - 10 Nov 2022

Cited by 1 | Viewed by 1459

Abstract

In this review, we describe previous basic and clinical studies on autonomous aldosterone production. Over the past decades, mineralocorticoid receptor antagonists (MRAs) have been found to concentration-dependently inhibit steroidogenesis in different degrees. However, many studies have proven the suppressive effects of MRAs on the activities of hormone synthase. The probable factors of cytochrome P-450 reduction, both in microsomes and mitochondria, have also been considered: (1) one of the spironolactone metabolite forms had destructive function, except canrenone, (2) 7α-thio-spironolactone was an obligatory intermediate in the spironolactone-induced CYP450 decrease, and (3) the contributing steroids should have 7α-methylthio or 7α-methylsulfone groups. In previous clinical research, spironolactone-body-containing cells showed a type II pattern of enzyme activity (i.e., enhanced 3β-hydroxysteroid dehydrogenase, glucose-6-phosphate, and NADP-isocitrate dehydrogenase activities and weaken succinate dehydrogenase activity), and the subcapsular micronodules composed of spironolactone-body-containing cells also exhibited a type II pattern and excess aldosterone secretion, indicating that the subcapsular micronodules might be the root of aldosterone-producing adenoma. Moreover, combined with the potential impeditive function to aldosterone secretion, a few cases of spontaneous remission of primary aldosteronism, with normal ranges of blood pressure, plasma potassium, plasma renin activity, and aldosterone renin ratio, have been reported after long-term treatment with MRAs. Full article

(This article belongs to the Special Issue New Paradigms in Aldosterone and Mineralocorticoid Receptor Pathophysiology)

23 pages, 989 KiB

Open AccessReview

Importance of Micromilieu for Pathophysiologic Mineralocorticoid Receptor Activity—When the Mineralocorticoid Receptor Resides in the Wrong Neighborhood

by Bruno Griesler, Christin Schuelke, Christian Uhlig, Yekaterina Gadasheva and Claudia Grossmann

Int. J. Mol. Sci. 2022, 23(20), 12592; https://doi.org/10.3390/ijms232012592 - 20 Oct 2022

Cited by 1 | Viewed by 1779

Abstract

The mineralocorticoid receptor (MR) is a member of the steroid receptor family and acts as a ligand-dependent transcription factor. In addition to its classical effects on water and electrolyte balance, its involvement in the pathogenesis of cardiovascular and renal diseases has been the subject of research for several years. The molecular basis of the latter has not been fully elucidated, but an isolated increase in the concentration of the MR ligand aldosterone or MR expression does not suffice to explain long-term pathologic actions of the receptor. Several studies suggest that MR activity and signal transduction are modulated by the surrounding microenvironment, which therefore plays an important role in MR pathophysiological effects. Local changes in micromilieu, including hypoxia, ischemia/reperfusion, inflammation, radical stress, and aberrant salt or glucose concentrations affect MR activation and therefore may influence the probability of unphysiological MR actions. The surrounding micromilieu may modulate genomic MR activity either by causing changes in MR expression or MR activity; for example, by inducing posttranslational modifications of the MR or novel interaction with coregulators, DNA-binding sites, or non-classical pathways. This should be considered when developing treatment options and strategies for prevention of MR-associated diseases. Full article

(This article belongs to the Special Issue New Paradigms in Aldosterone and Mineralocorticoid Receptor Pathophysiology)

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23 pages, 1428 KiB

Open AccessReview

Nonsteroidal Mineralocorticoid Receptor Antagonism by Finerenone—Translational Aspects and Clinical Perspectives across Multiple Organ Systems

by Peter Kolkhof, Robert Lawatscheck, Gerasimos Filippatos and George L. Bakris

Int. J. Mol. Sci. 2022, 23(16), 9243; https://doi.org/10.3390/ijms23169243 - 17 Aug 2022

Cited by 13 | Viewed by 5619

Abstract

Perception of the role of the aldosterone/mineralocorticoid receptor (MR) ensemble has been extended from a previously renal epithelial-centered focus on sodium and volume homeostasis to an understanding of their role as systemic modulators of reactive oxygen species, inflammation, and fibrosis. Steroidal MR antagonists (MRAs) are included in treatment paradigms for resistant hypertension and heart failure with reduced ejection fraction, while more recently, the nonsteroidal MRA finerenone was shown to reduce renal and cardiovascular outcomes in two large phase III trials (FIDELIO-DKD and FIGARO-DKD) in patients with chronic kidney disease and type 2 diabetes, respectively. Here, we provide an overview of the pathophysiologic role of MR overactivation and preclinical evidence with the nonsteroidal MRA finerenone in a range of different disease models with respect to major components of the aggregate mode of action, including interfering with reactive oxygen species generation, inflammation, fibrosis, and hypertrophy. We describe a time-dependent effect of these mechanistic components and the potential modification of major clinical parameters, as well as the impact on clinical renal and cardiovascular outcomes as observed in FIDELIO-DKD and FIGARO-DKD. Finally, we provide an outlook on potential future clinical indications and ongoing clinical studies with finerenone, including a combination study with a sodium–glucose cotransporter-2 inhibitor. Full article

(This article belongs to the Special Issue New Paradigms in Aldosterone and Mineralocorticoid Receptor Pathophysiology)

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13 pages, 1150 KiB

Open AccessReview

Mineralocorticoid Receptor Activation in Vascular Insulin Resistance and Dysfunction

by Aderonke E. Igbekele, George Jia, Michael A. Hill, James R. Sowers and Guanghong Jia

Int. J. Mol. Sci. 2022, 23(16), 8954; https://doi.org/10.3390/ijms23168954 - 11 Aug 2022

Cited by 6 | Viewed by 4102

Abstract

Systemic insulin resistance is characterized by reduced insulin metabolic signaling and glucose intolerance. Mineralocorticoid receptors (MRs), the principal receptors for the hormone aldosterone, play an important role in regulating renal sodium handling and blood pressure. Recent studies suggest that MRs also exist in tissues outside the kidney, including vascular endothelial cells, smooth muscle cells, fibroblasts, perivascular adipose tissue, and immune cells. Risk factors, including excessive salt intake/salt sensitivity, hypertension, and obesity, can lead to the activation of vascular MRs to promote inflammation, oxidative stress, remodeling, and fibrosis, as well as cardiovascular stiffening and microcirculatory impairment. These pathophysiological changes are associated with a diminished ability of insulin to initiate appropriate intracellular signaling events, resulting in a reduced glucose uptake within the microcirculation and related vascular insulin resistance. Therefore, the pharmacological inhibition of MR activation provides a potential therapeutic option for improving vascular function, glucose uptake, and vascular insulin sensitivity. This review highlights recent experimental and clinical data that support the contribution of abnormal MR activation to the development of vascular insulin resistance and dysfunction. Full article

(This article belongs to the Special Issue New Paradigms in Aldosterone and Mineralocorticoid Receptor Pathophysiology)

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