A New Mode of Mineralocorticoid Receptor Antagonism by a Potent and Selective Nonsteroidal Molecule

Fagart, Jérôme; Hillisch, Alexander; Huyet, J.; Bärfacker, Lars; Fay, Michèle; Pleiß, U.; Pook, Elisabeth; Schäfer, Stefan; Rafestin‐Oblin, Marie‐Edith; Kolkhof, Peter

doi:10.1074/jbc.m110.131342

Cited by 162 publications

(157 citation statements)

References 40 publications

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“…These antagonists regulate pro-inflammatory adipokines and ROS-related genes to ameliorate adipocyte dysfunction. However, Spir causes undesirable side effects because of its poor selectivity [41] , while Eple is less potent than Spir [42] . Therefore, discovering novel non-steroidal specific small-molecule ligands of MR is of great interest in diabetes therapy.…”

Section: Discussionmentioning

confidence: 99%

“…MR is a metabolic nuclear receptor that plays a key role in the regulation of electrolyte homeostasis and blood pressure in the body [12] . MR activation mediates inflammation, proliferation and fibrosis [29,39,40] , while MR blockade exhibits beneficial effects on cardiovascular morbidity and mortality in patients with heart failure [41,42] . Recent studies have also shown that MR antagonists improve adipocyte dysfunction and insulin resistance in obese mice [31][32][33] .…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies have also shown that MR antagonists improve adipocyte dysfunction and insulin resistance in obese mice [31][32][33] . The two MR antagonists, Spir and Eple, have been used clinically as antihypertensive drugs [41,42] . These antagonists regulate pro-inflammatory adipokines and ROS-related genes to ameliorate adipocyte dysfunction.…”

Section: Discussionmentioning

confidence: 99%

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Marine natural product des-O-methyllasiodiplodin effectively lowers the blood glucose level in db/db mice via ameliorating inflammation

et al. 2013

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Aim: des-O-methyllasiodiplodin (DML) from Cerbera manghas has shown antagonistic activity against mineralocorticoid receptor (MR). Considering the involvement of MR in the insulin tolerance, we attempted to investigate the potential of DML in the treatment of type 2 diabetes mellitus (T2DM). Methods: Surface plasmon resonance (SPR) technology and reporter gene-based assays were used to study protein-small molecule interactions. HepG2 and 3T3-L1 cells were treated with H 2 O 2 (0.2 mmol/L) or aldosterone (10 nmol/L) for 24 h. The expression of MR in the cells was downregulated with siRNA. The anti-inflammatory effect of the compound was evaluated, respectively. db/db mice were administered DML (30 mg· kg -1 ·d -1 ) for 4 weeks. Serum biochemical parameters and insulin sensitivity were examined. The expression levels of pro-inflammatory cytokines (MCP-1, TNF-α, and IL-6) and ROS-related genes (NADPH p47 subunit and transcriptional factor PU.1) in adipose tissues and livers were analyzed using real-time RT-PCR. Results: In HepG2 and 3T3-L1 cells, both H 2 O 2 and aldosterone markedly stimulates the expression of MCP-1, TNFα, IL-6, p47, and PU.1 genes. Co-treatment with DML (10 µmol/L) significantly reduced the H 2 O 2 -or aldosterone-induced expression of these genes. SPR-based assay confirmed the antagonistic activity of DML against the interaction between SRC-1 and MR-LBD. Furthermore, DML decreased aldosterone-induced MR transcriptional activity in a dose-dependent manner. Downregulation of MR with siRNA in the cells prevented or significantly attenuated aldosterone-stimulated expression of these genes, whereas DML did no longer affect the expression of these genes except that of IL-6. Oral administration of DML effectively reduced the levels of blood glucose and glycosylated hemoglobin (HbA1c) in db/db mice. The treatment also rectified the expression of pro-inflammatory factor and ROS-related genes in db/db mice. Conclusion: DML effectively lowers the blood glucose level in db/db mice possibly via ameliorating the expression of obesity-related pro-inflammatory cytokines, highlighting the potential of the marine natural product as a drug lead for the treatment of metabolic disorders.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Marine natural product des-O-methyllasiodiplodin effectively lowers the blood glucose level in db/db mice via ameliorating inflammation

et al. 2013

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“…The MR antagonist spironolactone (Sigma) is a widely used therapeutic drug with well characterized clinical and biochemical properties. BR-4628 (Bayer Pharma AG) is a new MR antagonist derived from the chemical structure of dihydropyridines with a advanced specificity for the MR (27). BR-4628 and spironolactone exhibit a similar IC 50 at the MR and were, therefore, used in the same concentrations (500 nM).…”

Section: Methodsmentioning

confidence: 99%

“…BR-4628 and spironolactone exhibit a similar IC 50 at the MR and were, therefore, used in the same concentrations (500 nM). This concentration is based on pharmacological studies to inhibit the MR activation by aldosterone binding (27). CN03 (Cytoskeleton) is a RhoA activator with an active site based on the catalytic domain of the bacterial cytotoxic necrotizing factor toxins.…”

Section: Methodsmentioning

confidence: 99%

The Mineralocorticoid Receptor Promotes Fibrotic Remodeling in Atrial Fibrillation

Lavall

Selzer

Schuster

et al. 2014

Journal of Biological Chemistry

106

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Background:We studied the role of the mineralocorticoid receptor (MR) for atrial fibrotic remodeling. Results: Increased 11␤-hydroxysteroid dehydrogenase type 2 in atrial fibrillation enhances mineralocorticoid receptor profibrotic signaling through connective tissue growth factor, lysyl oxidase, and microRNA-21. Conclusion:The MR regulates fibrogenesis in atrial fibrillation. Significance: The MR may represent a target for the prevention of atrial fibrosis.

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Renoprotective Effects of Mineralocorticoid Receptor Antagonists Against Diabetic Kidney Disease

Bayne,

LeFevre,

Olstinske

et al. 2023

Advanced Biology

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Diabetic kidney disease (DKD) is a growing epidemic worldwide and a leading cause of end‐stage kidney disease. Mineralocorticoid receptor (MR) blockade using Finerenone is a recently approved therapeutic approach to slow down the progression of DKD in patients with type 2 diabetes in addition to other therapies such as angiotensin‐II converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), sodium‐glucose co‐transporter 2 (SGLT2) inhibitors, and glucagon‐like peptide 1 (GLP‐1) analogs. This review elaborates on the pathophysiologic pathways activated by aldosterone (the human mineralocorticoid) in DKD, the pharmacology of three different generations of mineralocorticoid receptor antagonists (MRAs), specifically, spironolactone, eplerenone, and finerenone, and the mechanisms by which these MRAs elicit their protective effects on the kidney under diabetic settings.

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A New Mode of Mineralocorticoid Receptor Antagonism by a Potent and Selective Nonsteroidal Molecule

Cited by 162 publications

References 40 publications

Marine natural product des-O-methyllasiodiplodin effectively lowers the blood glucose level in db/db mice via ameliorating inflammation

Marine natural product des-O-methyllasiodiplodin effectively lowers the blood glucose level in db/db mice via ameliorating inflammation

The Mineralocorticoid Receptor Promotes Fibrotic Remodeling in Atrial Fibrillation

Renoprotective Effects of Mineralocorticoid Receptor Antagonists Against Diabetic Kidney Disease

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