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John W. Funder - One of the best experts on this subject based on the ideXlab platform.
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aldosterone and Mineralocorticoid receptors in the cardiovascular system
Progress in Cardiovascular Diseases, 2010Co-Authors: John W. FunderAbstract:Abstract Aldosterone is currently thought to exert its physiologic effects by activating epithelial Mineralocorticoid receptors, and its pathologic effects on the cardiovascular system via Mineralocorticoid receptors in the heart and blood vessels. Recent studies have extended this understanding to include a reevaluation of the roles of aldosterone and Mineralocorticoid receptor activation in blood pressure control; the rapid, nongenomic effects of aldosterone; the role of cortisol as a Mineralocorticoid receptor agonist under conditions of redox change/tissue damage/reactive oxygen species generation; the growing consensus that primary aldosteronism accounts for approximately 10% of all essential hypertension; recent new insights into the cardioprotective role of spironolactone; and the development of third- and fourth-generation Mineralocorticoid receptor antagonists for use in cardiovascular and other inflammatory disease. These findings on aldosterone action and Mineralocorticoid receptor blockade are analyzed in the context of the prevention and treatment of cardiovascular disease.
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Mineralocorticoid Receptors, Salt, and Hypertension
Recent progress in hormone research, 1997Co-Authors: John W. Funder, Karen E Sheppard, Zygmunt S. Krozowski, Kathy Myles, Atsuhisa Sato, Morag J YoungAbstract:This review, covering work from the Baker Institute and elsewhere, is divided into four sections. In the first a summary account of two areas-Mineralocorticoid receptors and the enzyme 11 beta hyderoxysteroid dehydrogenase-will be given as background. Next is a brief consideration of the three single-gene causes of human hypertension described to date-glucocorticoid-remediable aldosteronism. Liddle's syndrome, and apparent Mineralocorticoid excess-in all of which abnormal sodium handling is a feature. Third, the sequelae of aldosterone occupancy of nonepithelial Mineralocorticoid receptors will be analyzed in some detail by reviewing studies on experimental Mineralocorticoid hypertension and cardiac fibrosis from this laboratory and elsewhere. Finally, three recent studies from this laboratory will be presented: on putative 11-ketosteroid receptors in epithelial tissue, on glucose-PKC potentiation of Mineralocorticoid effects on heart cells, and on the necessity for factors/ processes other than the conversion of cortisol to cortisone (or, in the rat, corticosterone to 11-dehydrocorticosterone) to ensure aldosterone-specific effects in Mineralocorticoid target tissues.
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glucocorticoid and Mineralocorticoid receptors biology and clinical relevance
Annual Review of Medicine, 1997Co-Authors: John W. FunderAbstract:▪ Abstract Mineralocorticoid and glucocorticoid receptors act as homodimers via canonical pentadecamer hormone response elements to regulate transcription. Glucocorticoid, but as yet not Mineralocorticoid, receptors have been shown also to modulate AP-1- and NFκB-induced transcription by direct protein-protein interactions. The role of 11β-hydroxysteroid dehydrogenase in conferring aldosterone specificity on epithelial Mineralocorticoid receptors has been proven by the demonstration of sequence mutations in all cases of apparent Mineralocorticoid excess examined to date. The autosomal form of aldosterone resistance (pseudohypoaldosteronism) has been shown to reflect loss-of-function mutations in epithelial sodium channel subunit sequence. (Patho)physiological roles for aldosterone and glucocorticoid membrane receptors, and for the recently described nuclear receptors for 11–ketosteroids in 11β–hydroxysteroid dehydrogenase–protected epithelia, remain to be established.
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Mineralocorticoid receptors and hypertension
The Journal of Steroid Biochemistry and Molecular Biology, 1995Co-Authors: John W. FunderAbstract:Abstract Mineralocorticoid receptors (MR) have equal affinity for the Mineralocorticoid aldosterone, and the physiological glucocorticoids cortisol and corticosterone. In epithelial tissues in vivo , MR are protected against glucocorticoid occupancy by the enzyme 11β-hydroxysteroid dehydrogenase, allowing access by the lower circulating levels of the physiological Mineralocorticoid aldosterone. In non-epithelial tissues, including the heart and most areas of the central nervous system, MR are not so protected, and their physiological ligand is cortisol/corticosterone. Intracerebroventricular infusion studies have shown that aldosterone occupancy of such unprotected circumventricular MR is necessary for Mineralocorticoid hypertension, and the hypertensinogenic effects of peripherally infused aldosterone can be blocked by intracerebroventricular infusion of the MR antagonist RU28318. Prolonged (8 weeks) administration of Mineralocorticoids to salt-loaded rats has been shown to be followed by hypertension, cardiac hypertrophy and cardiac fibrosis. Whether the hypertrophy and fibrosis reflect primary effects of aldosterone via cardiac MR, or effects secondary to occupancy of protected, epithelial MR, remains to be determined, as does the mechanism of action of salt loading in this model of Mineralocorticoid hypertension.
Yoshio Yazaki - One of the best experts on this subject based on the ideXlab platform.
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5α-dihydro-11-deoxycorticosterone as a Mineralocorticoid agonist and antagonist: Evidence for a weak Mineralocorticoid as an antagonist of potent Mineralocorticoids
The Journal of steroid biochemistry and molecular biology, 1993Co-Authors: Hisahiko Sekihara, Yoshio YazakiAbstract:Abstract To evaluate the possibility that 5α-dihydro-11-deoxycorticosterone (5α-DH-DOC), a weak Mineralocorticoid, is an antagonist of a more potent Mineralocorticoid, aldosterone, 0.25 μg aldosterone was injected into adrenalectomized rats simultaneously with 200–800 μg 5α-DH-DOC and urinary Na/K ratio and Na and K excretion were evaluated. Urinary Na/K ratio and Na excretion were significantly lower than those of control rats regardless of whether rats were treated with 0.25 μg aldosterone alone or 400–800 μg 5α-DH-DOC alone. Urinary Na/K ratio and Na excretion of rats given a combination of 0.25 μg aldosterone plus 400–800 μg 5α-DH-DOC were significantly higher than those of rats given 0.25 μg aldosterone alone. None of the treatment caused significant changes in urinary K excretion. The results demonstrate that 5α-DH-DOC, a weak Mineralocorticoid, is an antagonist of the sodium-retaining action of a more potent Mineralocorticoid, aldosterone. Progesterone which has weak Mineralocorticoid activity is also known as an antagonist of more potent Mineralocorticoids. The results of the present study demonstrate further evidence that weak Mineralocorticoids may work as antagonists of more potent Mineralocorticoids.
Nicolette Farman - One of the best experts on this subject based on the ideXlab platform.
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Neutrophil Gelatinase–Associated Lipocalin, a Novel Mineralocorticoid Biotarget, Mediates Vascular Profibrotic Effects of Mineralocorticoids
Hypertension, 2015Co-Authors: Antoine Tarjus, Nicolette Farman, Ernesto Martínez-martínez, Celine Latouche, Thorsten Berger, Renaud Fay, Cristian Amador, Soumaya El Moghrabi, Tak Mak, Patrick RossignolAbstract:Activation of the Mineralocorticoid receptor has been shown to be deleterious in cardiovascular diseases (CVDs). We have recently shown that lipocalin 2 (Lcn2), or neutrophil gelatinase-associated lipocalin (NGAL), is a primary target of aldosterone/Mineralocorticoid receptor in the cardiovascular system. Lcn2 is a circulating protein, which binds matrix metalloproteinase 9 and modulates its stability. We hypothesized that Lcn2 could be a mediator of aldosterone/Mineralocorticoid receptor profibrotic effects in the cardiovascular system. Correlations between aldosterone and profibrotic markers, such as procollagen type I N-terminal peptide, were investigated in healthy subjects and subjects with abdominal obesity. The implication of Lcn2 in the Mineralocorticoid pathway was studied using Lcn2 knockout mice subjected to a nephrectomy/aldosterone/salt (NAS) challenge for 4 weeks. In human subjects, NGAL/matrix metalloproteinase 9 was positively correlated with plasma aldosterone and fibrosis biomarkers. In mice, loss of Lcn2 prevented the NAS-induced increase of plasma procollagen type I N-terminal peptide, as well as the increase of collagen fibers deposition and collagen I expression in the coronary vessels and the aorta. The lack of Lcn2 also blunted the NAS-induced increase in systolic blood pressure. Ex vivo, treatment of human fibroblasts with recombinant Lcn2 induced the expression of collagen I and the profibrotic galectin-3 and cardiotrophin-1 molecules. Our results showed that Lcn2 plays a key role in aldosterone/Mineralocorticoid receptor-mediated vascular fibrosis. The clinical data indicate that this may translate in human patients. Lcn2 is, therefore, a new biotarget in cardiovascular fibrosis induced by Mineralocorticoid activation.
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Neutrophil Gelatinase-Associated Lipocalin, a Novel Mineralocorticoid Biotarget, Mediates Vascular Profibrotic Effects of Mineralocorticoids.
Hypertension (Dallas Tex. : 1979), 2015Co-Authors: Antoine Tarjus, Soumaya El Moghrabi, Nicolette Farman, Cristián A. Amador, Ernesto Martínez-martínez, Celine Latouche, Thorsten Berger, Tak W. Mak, Renaud Fay, Patrick RossignolAbstract:Activation of the Mineralocorticoid receptor has been shown to be deleterious in cardiovascular diseases (CVDs). We have recently shown that lipocalin 2 (Lcn2), or neutrophil gelatinase-associated lipocalin (NGAL), is a primary target of aldosterone/Mineralocorticoid receptor in the cardiovascular system. Lcn2 is a circulating protein, which binds matrix metalloproteinase 9 and modulates its stability. We hypothesized that Lcn2 could be a mediator of aldosterone/Mineralocorticoid receptor profibrotic effects in the cardiovascular system. Correlations between aldosterone and profibrotic markers, such as procollagen type I N-terminal peptide, were investigated in healthy subjects and subjects with abdominal obesity. The implication of Lcn2 in the Mineralocorticoid pathway was studied using Lcn2 knockout mice subjected to a nephrectomy/aldosterone/salt (NAS) challenge for 4 weeks. In human subjects, NGAL/matrix metalloproteinase 9 was positively correlated with plasma aldosterone and fibrosis biomarkers. In mice, loss of Lcn2 prevented the NAS-induced increase of plasma procollagen type I N-terminal peptide, as well as the increase of collagen fibers deposition and collagen I expression in the coronary vessels and the aorta. The lack of Lcn2 also blunted the NAS-induced increase in systolic blood pressure. Ex vivo, treatment of human fibroblasts with recombinant Lcn2 induced the expression of collagen I and the profibrotic galectin-3 and cardiotrophin-1 molecules. Our results showed that Lcn2 plays a key role in aldosterone/Mineralocorticoid receptor-mediated vascular fibrosis. The clinical data indicate that this may translate in human patients. Lcn2 is, therefore, a new biotarget in cardiovascular fibrosis induced by Mineralocorticoid activation.
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Mineralocorticoid selectivity: molecular and cellular aspects.
Kidney international, 2000Co-Authors: Nicolette Farman, Brigitte BocchiAbstract:Mineralocorticoid selectivity: Molecular and cellular aspects. Aldosterone acts in Mineralocorticoid-sensitive cells by binding to the Mineralocorticoid receptor (MR). Because the MR displays similar affinity for aldosterone and glucocorticoid hormones and because these latter hormones are 100- to 1000-fold more abundant than aldosterone in the plasma, mechanisms are required to avoid permanent illicit occupancy of MR by glucocorticoid hormones. The main mechanism of Mineralocorticoid selectivity is enzymatic: the 11β hydroxysteroid dehydrogenase (HSD2) metabolizes glucocorticoid hormones into derivatives with a low affinity for MR. The cell biology and regulation of HSD2 are reviewed in this article, as well as its implications in human hypertension. Other factors play a role in Mineralocorticoid selectivity: the MR itself, the possibility to form homodimers (MR-MR), or heterodimers (with the glucocorticoid receptor). All of these cellular events participate to successive dynamic equilibriums, which allow fine tuning of transcriptional regulation of target genes, depending on the target tissue and the hormonal status.
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Molecular and cellular determinants of Mineralocorticoid selectivity
Current opinion in nephrology and hypertension, 1999Co-Authors: Nicolette FarmanAbstract:Aldosterone plays a major role in the regulation of renal sodium reabsorption, of extracellular fluid volume and blood pressure. Such specific Mineralocorticoid physiological adaptations occur despite the large prevalence of glucocorticoid hormones over aldosterone in the plasma. Indeed both classes of hormones bind with the same affinity to the Mineralocorticoid receptor, but several mechanisms allow selective and tissue-specific aldosterone effects. They represent a series of mutually interacting selectivity filters, which have not yet been fully documented. The main determinants of aldosterone selective effects include an enzymatic protection of the Mineralocorticoid receptor, the intrinsic properties of the Mineralocorticoid receptor towards different ligands, and numerous possibilities of interaction between corticosteroid receptors (forming different homo or heterodimers) and other transcription factors.
Christopher R. W. Edwards - One of the best experts on this subject based on the ideXlab platform.
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Cellular selectivity of aldosterone action: role of 11 beta-hydroxysteroid dehydrogenase.
Current opinion in nephrology and hypertension, 1995Co-Authors: Rafn Benediktsson, Brian R. Walker, Christopher R. W. EdwardsAbstract:Mineralocorticoid receptors in the distal nephron have no intrinsic specificity for Mineralocorticoids over glucocorticoids (cortisol in humans; corticosterone in rodents), but are protected from glucocorticoids by the enzyme 11 beta-hydroxysteroid dehydrogenase, which inactivates these steroids to cortisone and 11-dehydrocorticosterone, respectively. Recent work has demonstrated that the enzyme is expressed as multiple tissue-specific isoforms, some of which catalyse the reverse conversion of cortisone to cortisol. These isoforms may allow 11 beta-hydroxysteroid dehydrogenase to modulate access of ligands to glucocorticoid and Mineralocorticoid receptors, as well as to amplify and attenuate tissue responses. 11 beta-hydroxysteroid dehydrogenase-mediated protection of Mineralocorticoid receptors fails in congenital 11 beta-hydroxysteroid dehydrogenase deficiency and after inhibition of the enzyme by liquorice. In these circumstances, cortisol-dependent Mineralocorticoid excess and hypertension ensue. Recent studies suggest that similar deficiencies of 11 beta-dehydrogenase activity may contribute to pathophysiology in common clinical syndromes, illustrating the potential significance of this novel mechanism for development of hypertension.
Frederic Jaisser - One of the best experts on this subject based on the ideXlab platform.
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Vascular Mineralocorticoid receptor activation and disease.
Experimental eye research, 2019Co-Authors: Jonatan Barrera-chimal, Frederic JaisserAbstract:Abstract Mineralocorticoid receptor activation in endothelial and smooth muscle cells can promote vascular disease by increasing oxidative stress, promoting inflammation, accelerating vascular stiffness, remodeling, and calcification, altering vessel responsiveness to various vasoactive factors, thus altering vascular tone and blood pressure, and by altering angiogenesis. Here, we review the recent evidence highlighting the impact of vascular Mineralocorticoid receptor activation in pathological situations, including kidney injury, vascular injury associated with metabolic diseases, atherosclerosis, cerebral vascular injury during hypertension, vascular stiffening and aging, pulmonary hypertension, vascular calcification, cardiac remodeling, wound healing, inflammation, thrombosis, and disorders related to angiogenic defects in the eye. The possible mechanisms implicating Mineralocorticoid receptor activation in various vascular disorders are discussed. Altogether, recent evidence points towards pharmacological Mineralocorticoid receptor inhibition as a strategy to treat diseases in which overactivation of the Mineralocorticoid receptor in endothelial and/or smooth muscle cells may play a pivotal role.
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The myeloid Mineralocorticoid receptor controls inflammatory and fibrotic responses after renal injury via macrophage interleukin-4 receptor signaling
Kidney International, 2018Co-Authors: Jonatan Barrera-chimal, Peter Kolkhof, Sebastian M Lechner, Soumaya El Moghrabi, Gabriel R. Estrela, Shiem Kaaki, Sébastien Giraud, Thierry Hauet, Frederic JaisserAbstract:Acute kidney injury induced by ischemia/reperfusion is an independent risk factor for chronic kidney disease. Macrophage recruitment plays an essential role during the injury and repair phases after an ischemic episode in the kidney. Here we show that the novel non-steroidal Mineralocorticoid receptor antagonist finerenone or selective myeloid Mineralocorticoid receptor ablation protects against subsequent chronic dysfunction and fibrosis induced by an episode of bilateral kidney ischemia/reperfusion in mice. This protection was associated with increased expression of M2-antiinflamatory markers in macrophages from finerenone-treated or myeloid Mineralocorticoid receptor-deficient mice. Moreover, the inflammatory population of CD11b + , F4/80 + , Ly6C high macrophages was also reduced. Mineralocorticoid receptor inhibition promoted increased IL-4 receptor expression and activation in the whole kidney and in isolated macrophages, thereby facilitating macrophage polarization to an M2 phenotype. The long-term protection conferred by Mineralocorticoid receptor antagonism was also translated to the Large White pig pre-clinical model. Thus, our studies support the rationale for using Mineralocorticoid receptor antagonists in clinical practice to prevent transition of acute kidney injury to chronic kidney disease.
