Mineralocorticoid Receptor Antagonists: a Comprehensive Review of Finerenone

White, Averi; Ahmadian-Tehrani, Ashkan; Anderson, Allen S.

doi:10.1007/s11886-020-01399-7

Cited by 55 publications

(56 citation statements)

References 47 publications

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“…The human AGT promoter possesses a number of CpG dinucleotides that are targets for DNA methylation ( Figure 2 ). The human AGT promoter which is located within a CCAAT enhancer-binding protein (CEBP)-binding site that contains a CpG dinucleotide at positions −218/−217, is hypomethylated in tissues and cells with high AGT expression (liver, heart and HepG2 hepatocytes) but not in those with low expression (adrenal glands, leukocytes and adrenocortical H295R cells) [ 16 ]. Thus, the methylation status of a CpG dinucleotide within the CEBP-binding site appears to be inversely associated with AGT expression.…”

Section: Contribution Of Dna Methylation To Human Agt Gene Transcriptionmentioning

confidence: 99%

“…CEBP has a pivotal role in the transcriptional regulation of the AGT gene in both humans and rats [ 16 ]. Two CEBP-binding sites (CTTGCTCCA, positions +2 to +10; and CTGGGAA, positions +78 to +84) exist in the first exon of the rat AGT gene.…”

Section: Effect Of Salt Intake On Methylation Status Of the Agt Gene In The Heartmentioning

confidence: 99%

“…Aldosterone is produced in the zona glomerulosa of the adrenal cortex by aldosterone synthase (CYP11B2) and is known to promote cardiac fibrosis and hypertrophy with concurrent elevation of inflammatory and oxidant signaling [ 14 , 15 , 16 , 17 ]. Aldosterone synthesis is regulated by angiotensin II and potassium.…”

Section: Introductionmentioning

confidence: 99%

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DNA Methylation of the Angiotensinogen Gene, AGT, and the Aldosterone Synthase Gene, CYP11B2 in Cardiovascular Diseases

Takeda

Demura

Yoneda

et al. 2021

IJMS

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Angiotensinogen (AGT) and aldosterone play key roles in the regulation of blood pressure and are implicated in the pathogenesis of cardiovascular diseases. DNA methylation typically acts to repress gene transcription. The aldosterone synthase gene CYP11B2 is regulated by angiotensin II and potassium. DNA methylation negatively regulates AGT and CYP11B2 expression and dynamically changes in response to continuous promoter stimulation of each gene. High salt intake and excess circulating aldosterone cause DNA demethylation around the CCAAT-enhancer-binding-protein (CEBP) sites of the CYP11B2 promoter region, thereby converting the phenotype of AGT expression from an inactive to an active state in visceral adipose tissue and heart. A close association exists between low DNA methylation at CEBP-binding sites and increased AGT expression in salt-sensitive hypertensive rats. Salt-dependent hypertension may be partially affected by increased cardiac AGT expression. CpG dinucleotides in the CYP11B2 promoter are hypomethylated in aldosterone-producing adenomas. Methylation of recognition sequences of transcription factors, including CREB1, NGFIB (NR4A1), and NURR1 (NR4A2) diminish their DNA-binding activity. The methylated CpG-binding protein MECP2 interacts directly with the methylated CYP11B2 promoter. Low salt intake and angiotensin II infusion lead to upregulation of CYP11B2 expression and DNA hypomethylation in the adrenal gland. Treatment with the angiotensin II type 1 receptor antagonist decreases CYP11B2 expression and leads to DNA hypermethylation. A close association between low DNA methylation and increased CYP11B2 expression are seen in the hearts of patients with hypertrophic cardiomyopathy. These results indicate that epigenetic regulation of both AGT and CYP11B2 contribute to the pathogenesis of cardiovascular diseases.

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Section: Contribution Of Dna Methylation To Human Agt Gene Transcriptionmentioning

confidence: 99%

Section: Effect Of Salt Intake On Methylation Status Of the Agt Gene In The Heartmentioning

confidence: 99%

See 1 more Smart Citation

DNA Methylation of the Angiotensinogen Gene, AGT, and the Aldosterone Synthase Gene, CYP11B2 in Cardiovascular Diseases

Takeda

Demura

Yoneda

et al. 2021

IJMS

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“…Somit ist die Therapie der diabetischen Nephropathie weiterhin unbefriedigend. deutlich geringere Anstiege des Serumkaliums als Spironolacton, bei gleichzeitig effektiver Reduktion der Albuminurie und schon bestehender RAS-Blocker-Therapie [14].…”

Section: Finerenonunclassified

Finerenon

Hausberg¹

2021

Dialyse aktuell

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Die diabetische Nephropathie, eine Manifestation der diabetischen Mikroangiopathie, ist weiterhin die häufigste Ursache der terminalen dialysepflichtigen Niereninsuffizienz in den Industrienationen. Dies zeigen u. a. aktuelle Daten des Registers der „European Renal Association – European Dialysis and Transplant Association“ (ERA-EDTA) 1. Die Pathophysiologie der diabetischen Nephropathie ist komplex. Wesentliche Progressionsfaktoren sind Hyperfiltration und Inflammation neben mangelhafter Kontrolle des Glukosestoffwechsels (Abb. 2).

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“…Novel, non-steroidal MRAs, such as finerenone, may provide better cardio-protection against aldosterone`s cardio-toxic actions than the classic steroidal MRAs, such as sprironolactone and eplerenone [13,14]. Indeed, finerenone was recently shown to be a more potent and efficacious inverse agonist at the MR, compared to eplerenone, in terms of cardiac fibrosis/adverse remodeling attenuation [15].…”

Section: Introductionmentioning

confidence: 99%

GRK5 is an Essential Co-repressor for Cardiac Mineralocorticoid Receptor Antagonism induced by Finerenone but not Eplerenone

Desimine¹,

Ghandour²,

Cora³

et al. 2020

Preprint

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Background: In the heart, aldosterone (Aldo) binds the mineralocorticoid receptor (MR) to exert damaging, adverse remodeling-promoting effects. We recently showed that G protein-coupled receptor (GPCR)-kinase (GRK)-5 blocks the cardiac MR by directly phosphorylating it, thereby repressing its transcriptional activity. MR antagonist (MRA) drugs block the cardiac MR reducing morbidity and mortality of advanced human heart failure. Non-steroidal MRAs, such as finerenone, may provide better cardio-protection against Aldo than classic, steroidal MRAs, like spironolactone and eplerenone. Herein, we sought to investigate potential differences between finerenone and eplerenone at engaging GRK5-dependent cardiac MR phosphorylation and subsequent blockade. Methods: We used the cardiomyocyte cell line H9c2 and neonatal rat ventricular myocytes (NRVMs). Results: GRK5 phosphorylates the MR in H9c2 cardiomyocytes in response to finerenone but not to eplerenone. Unlike eplerenone, finerenone alone potently and efficiently suppresses cardiac MR transcriptional activity, thus displaying inverse agonism. GRK5 is necessary for finerenone`s inverse agonism, since GRK5 genetic deletion renders finerenone incapable of blocking cardiac MR transcriptional activity. Eplerenone alone does not fully suppress cardiac MR basal activity regardless of GRK5 expression levels. Finally in NRVMs, GRK5 is necessary for the anti-apoptotic and anti-fibrotic effects of both finerenone and eplerenone against Aldo, as well as for the higher efficacy and potency of finerenone at blocking Aldo-induced apoptosis and fibrosis. Conclusions: Finerenone, but not eplerenone, induces GRK5-dependent cardiac MR inhibition, which underlies, at least in part, its higher potency and efficacy, compared to eplerenone, as an MRA in the heart. GRK5 acts as a co-repressor of the cardiac MR and is essential for efficient MR antagonism in the myocardium.

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Mineralocorticoid Receptor Antagonists: a Comprehensive Review of Finerenone

Cited by 55 publications

References 47 publications

DNA Methylation of the Angiotensinogen Gene, AGT, and the Aldosterone Synthase Gene, CYP11B2 in Cardiovascular Diseases

DNA Methylation of the Angiotensinogen Gene, AGT, and the Aldosterone Synthase Gene, CYP11B2 in Cardiovascular Diseases

Finerenon

GRK5 is an Essential Co-repressor for Cardiac Mineralocorticoid Receptor Antagonism induced by Finerenone but not Eplerenone

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