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European Heart Journal Jan 2021This review covers the last 80 years of remarkable progress in the development of mineralocorticoid receptor (MR) antagonists (MRAs) from synthesis of the first... (Review)
Review
This review covers the last 80 years of remarkable progress in the development of mineralocorticoid receptor (MR) antagonists (MRAs) from synthesis of the first mineralocorticoid to trials of nonsteroidal MRAs. The MR is a nuclear receptor expressed in many tissues/cell types including the kidney, heart, immune cells, and fibroblasts. The MR directly affects target gene expression-primarily fluid, electrolyte and haemodynamic homeostasis, and also, but less appreciated, tissue remodelling. Pathophysiological overactivation of the MR leads to inflammation and fibrosis in cardiorenal disease. We discuss the mechanisms of action of nonsteroidal MRAs and how they differ from steroidal MRAs. Nonsteroidal MRAs have demonstrated important differences in their distribution, binding mode to the MR and subsequent gene expression. For example, the novel nonsteroidal MRA finerenone has a balanced distribution between the heart and kidney compared with spironolactone, which is preferentially concentrated in the kidneys. Compared with eplerenone, equinatriuretic doses of finerenone show more potent anti-inflammatory and anti-fibrotic effects on the kidney in rodent models. Overall, nonsteroidal MRAs appear to demonstrate a better benefit-risk ratio than steroidal MRAs, where risk is measured as the propensity for hyperkalaemia. Among patients with Type 2 diabetes, several Phase II studies of finerenone show promising results, supporting benefits on the heart and kidneys. Furthermore, finerenone significantly reduced the combined primary endpoint (chronic kidney disease progression, kidney failure, or kidney death) vs. placebo when added to the standard of care in a large Phase III trial.
Topics: Diabetes Mellitus, Type 2; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Mineralocorticoids; Spironolactone
PubMed: 33099609
DOI: 10.1093/eurheartj/ehaa736 -
British Journal of Pharmacology Jul 2022Mineralocorticoid receptor antagonists (MRAs) are key agents in guideline-oriented drug therapy for cardiovascular diseases such as chronic heart failure with reduced... (Review)
Review
Mineralocorticoid receptor antagonists (MRAs) are key agents in guideline-oriented drug therapy for cardiovascular diseases such as chronic heart failure with reduced ejection fraction and resistant hypertension. Currently available steroidal MRAs are efficacious in reducing morbidity and mortality; however, they can be associated with intolerable side effects including hyperkalaemia in everyday clinical practice. Recently, a new class of non-steroidal MRAs (including esaxerenone, AZD9977, apararenone, KBP-5074 and finerenone) have been developed with an improved benefit-risk profile and a novel indication for finerenone for diabetic kidney disease. To better understand the non-steroidal MRAs, this review provides information on the molecular pharmacology as well as relevant current preclinical and clinical data on cardiorenal outcomes. A comparative review of all compounds in the class is discussed with regard to clinical efficacy and safety as well as a perspective outlining their future use in clinical practice. LINKED ARTICLES: This article is part of a themed issue on Emerging Fields for Therapeutic Targeting of the Aldosterone-Mineralocorticoid Receptor Signaling Pathway. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.13/issuetoc.
Topics: Heart Failure; Humans; Hypertension, Renal; Mineralocorticoid Receptor Antagonists; Mineralocorticoids; Nephritis; Piperidines; Pyrazoles; Quinolines
PubMed: 34811750
DOI: 10.1111/bph.15747 -
Endocrinology Apr 2022
Topics: Aldosterone; Glucocorticoids; Mineralocorticoids; Receptors, Mineralocorticoid
PubMed: 35148380
DOI: 10.1210/endocr/bqac016 -
American Journal of Hypertension Feb 2023Steroidal mineralocorticoid-receptor-antagonists (MRAs), such as spironolactone and eplerenone, are guideline-directed therapies in patients with heart failure with... (Review)
Review
Steroidal mineralocorticoid-receptor-antagonists (MRAs), such as spironolactone and eplerenone, are guideline-directed therapies in patients with heart failure with reduced ejection fraction or resistant hypertension. However, the associated risk of hyperkalemia and hormonal side effects limit their broad use and downstream cardiorenal protection in high-risk patients with type 2 diabetes mellitus (T2DM) and moderate-to-advanced chronic kidney disease (CKD). The critical unmet need to improve long-term cardiorenal outcomes in such patients with CKD has sparked considerable efforts to the discovery and development of a new class of compounds. Finerenone is a novel, nonsteroidal MRA that has recently received regulatory approval with the indication of cardiorenal protection in patients with CKD associated with T2DM. Two landmark phase 3 clinical trials, FIDELIO-DKD and FIGARO-DKD, demonstrated that among patients with T2DM and a broad spectrum of CKD, finerenone reduced the risk of "hard" cardiovascular and kidney failure outcomes as compared with placebo, with a minimal risk of hyperkalemia. Subgroup analyses of these trials also provided preliminary evidence that the efficacy and safety profile of finerenone was similar and irrespective of background therapy with other guideline-directed therapies, such as sodium-glucose co-transporter type 2 (SGLT-2) inhibitors and glucagone-like peptide 1 receptor agonists. Whether the combination of finerenone with a SGLT-2 inhibitor is more beneficial in patients with T2DM and CKD as compared with either therapy alone is a crucial research question that is currently under investigation in an ongoing clinical trial.
Topics: Humans; Mineralocorticoid Receptor Antagonists; Diabetes Mellitus, Type 2; Mineralocorticoids; Hyperkalemia; Renal Insufficiency, Chronic
PubMed: 36331811
DOI: 10.1093/ajh/hpac124 -
International Journal of Molecular... Apr 2023Regulation and action of the mineralocorticoid receptor (MR) have been the focus of intensive research over the past 80 years. Genetic and physiological/biochemical... (Review)
Review
Regulation and action of the mineralocorticoid receptor (MR) have been the focus of intensive research over the past 80 years. Genetic and physiological/biochemical analysis revealed how MR and the steroid hormone aldosterone integrate the responses of distinct tubular cells in the face of environmental perturbations and how their dysregulation compromises fluid homeostasis. In addition to these roles, the accumulation of data also provided unequivocal evidence that MR is involved in the pathophysiology of kidney diseases. Experimental studies delineated the diverse pathological consequences of MR overactivity and uncovered the multiple mechanisms that result in enhanced MR signaling. In parallel, clinical studies consistently demonstrated that MR blockade reduces albuminuria in patients with chronic kidney disease. Moreover, recent large-scale clinical studies using finerenone have provided evidence that the non-steroidal MR antagonist can retard the kidney disease progression in diabetic patients. In this article, we review experimental data demonstrating the critical importance of MR in mediating renal injury as well as clinical studies providing evidence on the renoprotective effects of MR blockade. We also discuss areas of future investigation, which include the benefit of non-steroidal MR antagonists in non-diabetic kidney disease patients, the identification of surrogate markers for MR signaling in the kidney, and the search for key downstream mediators whereby MR blockade confers renoprotection. Insights into these questions would help maximize the benefit of MR blockade in subjects with kidney diseases.
Topics: Humans; Albuminuria; Aldosterone; Kidney; Mineralocorticoid Receptor Antagonists; Receptors, Mineralocorticoid; Renal Insufficiency, Chronic
PubMed: 37175424
DOI: 10.3390/ijms24097719 -
British Journal of Pharmacology Jul 2022In the retina, the mineralocorticoid receptor is expressed in retinal and choroidal vessels and in cells from neural and glial origins. Like in the brain, the major... (Review)
Review
In the retina, the mineralocorticoid receptor is expressed in retinal and choroidal vessels and in cells from neural and glial origins. Like in the brain, the major ligand of the mineralocorticoid receptor is cortisol, and the mineralocorticoid/glucocorticoid receptor balance regulates the activation of the MR pathway. Experimental mineralocorticoid receptor pathway activation using either pharmacological agents or transgenic manipulation favours retinal and choroidal pathology. In various models of retinal diseases, such as glaucomatous neuropathy, retinopathy of prematurity, ischaemic retinopathies, diabetic retinopathy and choroidal neovascularization, mineralocorticoid receptor antagonism exerts beneficial effects, demonstrating its potential in the treatment of major blinding retinal diseases. But specific formulations are required to optimize the bioavailability of mineralocorticoid receptor antagonists in various compartments of the eye, and molecular biomarkers of mineralocorticoid receptor pathway activation remain to be identified in humans to select patients amenable to clinical trials. LINKED ARTICLES: This article is part of a themed issue on Emerging Fields for Therapeutic Targeting of the Aldosterone-Mineralocorticoid Receptor Signaling Pathway. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.13/issuetoc.
Topics: Diabetic Retinopathy; Humans; Mineralocorticoid Receptor Antagonists; Mineralocorticoids; Receptors, Mineralocorticoid; Retina; Retinal Diseases
PubMed: 34877649
DOI: 10.1111/bph.15770 -
International Journal of Molecular... Aug 2022Systemic insulin resistance is characterized by reduced insulin metabolic signaling and glucose intolerance. Mineralocorticoid receptors (MRs), the principal receptors... (Review)
Review
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.
Topics: Aldosterone; Blood Pressure; Endothelial Cells; Glucose; Humans; Insulin; Insulin Resistance; Microcirculation; Mineralocorticoid Receptor Antagonists; Mineralocorticoids; Receptors, Mineralocorticoid
PubMed: 36012219
DOI: 10.3390/ijms23168954 -
The Journal of Clinical Investigation Jan 2024Mineralocorticoid excess commonly leads to hypertension (HTN) and kidney disease. In our study, we used single-cell expression and chromatin accessibility tools to...
Mineralocorticoid excess commonly leads to hypertension (HTN) and kidney disease. In our study, we used single-cell expression and chromatin accessibility tools to characterize the mineralocorticoid target genes and cell types. We demonstrated that mineralocorticoid effects were established through open chromatin and target gene expression, primarily in principal and connecting tubule cells and, to a lesser extent, in segments of the distal convoluted tubule cells. We examined the kidney-protective effects of steroidal and nonsteroidal mineralocorticoid antagonists (MRAs), as well as of amiloride, an epithelial sodium channel inhibitor, in a rat model of deoxycorticosterone acetate, unilateral nephrectomy, and high-salt consumption-induced HTN and cardiorenal damage. All antihypertensive therapies protected against cardiorenal damage. However, finerenone was particularly effective in reducing albuminuria and improving gene expression changes in podocytes and proximal tubule cells, even with an equivalent reduction in blood pressure. We noted a strong correlation between the accumulation of injured/profibrotic tubule cells expressing secreted posphoprotein 1 (Spp1), Il34, and platelet-derived growth factor subunit b (Pdgfb) and the degree of fibrosis in rat kidneys. This gene signature also showed a potential for classifying human kidney samples. Our multiomics approach provides fresh insights into the possible mechanisms underlying HTN-associated kidney disease, the target cell types, the protective effects of steroidal and nonsteroidal MRAs, and amiloride.
Topics: Rats; Humans; Animals; Mineralocorticoid Receptor Antagonists; Chromatin; Amiloride; Mineralocorticoids; Kidney; Hypertension; Kidney Diseases; Gene Expression Profiling
PubMed: 37906287
DOI: 10.1172/JCI157165 -
Hypertension (Dallas, Tex. : 1979) Feb 2019
Topics: Fibrosis; Heart Atria; Humans; Mineralocorticoids; Receptors, Mineralocorticoid
PubMed: 30595119
DOI: 10.1161/HYPERTENSIONAHA.118.11604