Steroidal and Non-steroidal Mineralocorticoid Receptor Antagonists in Cardiorenal Medicine

Rajiv Agarwal; Peter Kolkhof; George Bakris; Johann Bauersachs; Hermann Haller; Takashi Wada; Faiez Zannad

Eur Heart J. 2021;42(2):152-161.

Abstract and Introduction

Abstract

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.

Introduction

This review aims to provide an overview of the role of the mineralocorticoid receptor (MR) in inflammation and fibrosis and to discuss the discovery of agents that target the MR. We first explore steroidal MR antagonists (MRAs), such as spironolactone and eplerenone, and then the nonsteroidal MRAs. We also endeavour to conceptualize the molecular mechanisms of MR antagonism and downstream cardiorenal protection to better distinguish how the mechanisms of action of nonsteroidal MRAs differ from those of steroidal MRAs. Preclinical studies are described to set the stage for presenting nonsteroidal MRAs as a new treatment option in patients with cardiorenal disease. Specifically, in patients with Type 2 diabetes (T2D) and cardiorenal disease, we discuss why inflammation and fibrosis mediated by MR overactivation could present a novel treatment target beyond traditional treatments focusing primarily on metabolic and haemodynamic targets. Finerenone and esaxerenone are two new nonsteroidal MRAs under clinical development to treat patients with chronic kidney disease (CKD) and T2D.^[1–3]

1 2 3 4 5 6 7 8 9 10 11

Next Section

Table 1. Key differences between steroidal MRAs and nonsteroidal finerenone
	Steroidal MRAs		Nonsteroidal finerenone
Mode of MR antagonism	Spironolactone	Eplerenone	Finerenone Potent and selective⁵⁹ Bulky and passive⁶¹
	Potent and unselective (first generation)	Less potent and more selective than spironolactone (second generation)
	Passive
Tissue distribution (in rodents)	Spironolactone	Eplerenone	Finerenone: balanced kidney–heart⁶²
Tissue distribution (in rodents)	Kidney > heart⁶³	Kidney > heart⁶⁴	Finerenone: balanced kidney–heart⁶²
Pharmacokinetics	Spironolactone: prodrug with multiple active metabolites with long half-lives⁶⁵ Eplerenone: no active metabolites; half-life 4–6 h⁶⁴		Finerenone: no active metabolites and short half-life^66,67
Effect on cofactor recruitment in absence of aldosterone in vitro ^61,68	Spironolactone and eplerenone: partial agonistic cofactor recruitment		Finerenone: inverse agonist (inhibits cofactor binding in the absence of aldosterone)
Effect on cofactor recruitment in the presence of aldosterone in vitro	Spironolactone and eplerenone: inhibition of cofactor recruitment⁶⁸		Finerenone: more potent and efficacious than eplerenone in blocking MR cofactor binding and inducing corepressor binding⁶⁸
Effect on mutated (S810L) MR in vitro ⁶¹	Spironolactone and eplerenone: agonists		Finerenone: antagonist
Effect on inflammation and fibrosis in mouse model of cardiac fibrosis⁶⁸	Eplerenone (at equinatriuretic dose to finerenone): less significant effects on inflammation and fibrosis		Finerenone (at equinatriuretic dose to eplerenone): strong inhibition of inflammation and fibrosis
Effect on renal inflammation and fibrosis in a DOCA–salt rat model of CKD⁶²	Eplerenone (at equinatriuretic dose to finerenone): significant BP reduction; less efficacious proteinuria and renal injury reduction		Finerenone (at equinatriuretic dose to eplerenone): significant systolic BP reduction only at highest dosage; greater protection from cardiac and renal injury and structural remodelling; stronger inhibition of renal expression of pro-inflammatory and pro-fibrotic markers

BP, blood pressure; CKD, chronic kidney disease; DOCA, deoxycorticosterone acetate; MR, mineralocorticoid receptor; MRA, mineralocorticoid receptor antagonist.

Supplementary Table S1. Molecular insights from preclinical MR models
Model	Phenotype	Pathophysiology	Reference
Complete knock-out of the MR	Death within 10 days, pseudohypoaldosteronism	Increased renin, aldosterone and potassium; decreased sodium and ENaC in the kidney (24%) and colon (16%), but no change in mRNA abundance of ENaC	Berger 1998¹
Kidney-specific MR knock-out
Principal cell, renal tubule	Salt wasting, survival to adulthood. Sodium/water loss on low-sodium diet	Increased aldosterone; decreased ENaC in CCD, impaired trafficking	Ronzaud 2007²
Renal nephron	Severe pseudohypoaldosteronism-1. Death on sodium-deficient diet	Increased aldosterone and potassium; decreased sodium and ENaC-a; increased GR; decreased sodium chloride co-transporter downstream change to increased potassium	Canonica 2016;³ Terker 2016⁴
Cardiomyocyte-specific MR knock-out
Infarct-induced cardiac remodelling		Increased infarct healing and capillary density; decreased pulmonary oedema, progressive adverse cardiac remodelling, contractile dysfunction, and Nox2 upregulation; reduced ECM deposition; increased stress-induced activation and subsequent suppression of nuclear factor-κB and decreased apoptosis	Fraccarollo 2011⁵
DOCA–salt-induced cardiac inflammation and fibrosis		Similar recruitment of macrophages decreased cardiac inflammation and fibrosis at baseline, at 8 days and 8 weeks; increased decorin (at baseline and 8 weeks), mRNA and protein. BP response	Rickard 2012⁶
Uninephrectomy–salt ± DOCA, ischaemia reperfusion heart		MR excess. Increased peak contraction during ischaemia, regardless of genotype. Recovery of LV pressure and rates of contraction increased in KO. Incidence of arrhythmic activity during early reperfusion significantly higher in WT than in KO hearts	Bienvenu 2015⁷
Cell-specific MR knock-out
Vascular smooth muscle-specific MR knock-out	Decreased BP with age, without defects in renal sodium handling or vascular structure	Decreased vascular myogenic tone, agonist-dependent contraction, activity of L-type calcium channels; reduced ang II-induced vascular oxidative stress	McCurley 2012⁸
Endothelial cell-specific MR knock-out	DOCA–salt-induced cardiac fibrosis	Endothelial function better in response to aldosterone in conduit artery (aorta) but not resistance artery (mesenteric); cardiac inflammation less at 8 days, and fibrosis and inflammation less at 8 weeks. BP unchanged with WT or EC-MRKO	Rickard 2014⁹
MR deletion in podocytes	No different from WT mice; eplerenone was protective		Huang 2014¹⁰
MR deletion in myeloid cells	Albuminuria reduced on day 1; reduced tubular damage and fibrosis	Decreased cystatin C, crescents, macrophages and neutrophils; pro-inflammatory cytokines	Huang 2014¹⁰
Myeloid/macrophage-specific knock out of MR, with extra stimuli
DOCA–salt uninephrectomy	Decreased function of macrophages; similar recruitment of macrophages; reduced cardiac fibrosis and hypertension		Rickard 2009¹¹
Ang II/L-NAME	Macrophages from mice lacking MR in myeloid cells exhibited a transcription profile of alternative activation (in contrast to classical activation of M1 macrophages)	Cardiac hypertrophy, fibrosis and vascular damage. BP increased in KO, especially in PP and complete loss of PP circadian variation	Usher 2010¹²
Stroke–ischaemia reperfusion	Infarct volume reduced by 65%; decreased recruitment of macrophages; suppressed M1 macrophages and partially restored M2 macrophages		Frieler 2011¹³
Anti-Thy1 GN	Decreased fibrosis and inflammation, and proteinuria at 1 week compared with eplerenone, GFR protection		Huang 2014¹⁰
Salt ± DOCA. Cardiac fibrosis at 8 weeks	Activation of the c-Jun NH2-terminal kinase pathway in macrophages after a tissue injury and inflammatory stimuli in the DOCA–salt model is MR-dependent and regulates the transcription of downstream pro-fibrotic factors		Shen 2017¹⁴
Myeloid cell-restricted MR deletion by Cre-Lox recombination	Compared with WT controls, MRKO mice had: improved cardiac function and remodelling after MI; enhanced neutrophil efferocytosis; reduced superoxide production; improved post-ischaemic wound healing		Fraccarollo 2019¹⁵
MR overactivation
Human MR overexpression in MR-sensitive tissues	Renal and cardiac abnormalities including enlarged kidneys (associated with tubular dilation) and mild dilatated cardiomyopathy	Increased renal and cardiac SGK expression and increased cardiac ANP expression. Dilated cardiomyopathy not associated with induction of cardiac fibrosis	Le Menuet 2001¹⁶
Conditional cardiomyocyte-specific overexpression of the human MR	Embryonic and/or early postnatal lethality. High early mortality in surviving mice	Normal cardiac structure but functional heart defect predisposing to fatal arrhythmia. No increase in cardiac fibrosis or inflammation.	Ouvrard-Pascaud 2005¹⁷
Rac1 knockout mice	Podocytes undergo conversion to a motile phenotype	Podocyte injury, proteinuria, FSGS, cardiac hypertrophy, cardiomyopathy, heart failure, arrhythmia	Nagase 2013¹⁸

ang II, angiotensin II; ANP, atrial natriuretic peptide; BP, blood pressure; CCD, cortical-collecting duct; DOCA, deoxycorticosterone acetate; EC-MRKO, endothelial cell mineralocorticoid receptor knock-out; ECM, extracellular matrix; ENaC, endothelial sodium channel; FSGS, focal segmental glomerulosclerosis; GBM, glomerular basement membrane; GN, glomerulonephritis; GR, glucocorticoid receptor; KO, knock-out; LV, left ventricular; MI, myocardial infarction; MR, mineralocorticoid receptor; MRKO, mineralocorticoid receptor knock-out; PP, pulse pressure; SGK, serum and glucocorticoid-inducible kinase; WT, wild-type

Authors and Disclosures

Rajiv Agarwal¹*, Peter Kolkhof², George Bakris³, Johann Bauersachs⁴, Hermann Haller⁵, Takashi Wada⁶ and Faiez Zannad⁷

¹Indiana University School of Medicine and VA Medical Center, 1481 West 10th Street, 111N Indianapolis, IN 46202, USA; ²R&D Preclinical Research Cardiovascular, Bayer AG, Wuppertal, Germany; ³American Society of Hypertension's Comprehensive Hypertension Center at the University of Chicago Medicine, Chicago, IL, USA; ⁴Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany; ⁵Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany; ⁶Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Ishikawa, Japan; and ⁷Centre d'Investigations Cliniques Plurithématique, University Henri Poincaré, Nancy, France

*Corresponding author
Tel: +1 317 988 2241, Email: ragarwal@iu.edu

Conflict of interest
R.A. reports personal fees from Akebia, during the conduct of the study, personal fees from Bayer, personal fees from Abbvie, personal fees from Astra Zeneca, personal fees from Johnson and Johnson, personal fees from Boehringer Ingelheim, personal fees from Takeda, personal fees from Daiichi Sankyo, personal fees from Amgen, personal fees from Celgene, personal fees from Eli Lilly, personal fees from Relypsa, personal fees from Reata, personal fees from Opko, personal fees from ZS Pharma, and personal fees from Merck, outside the submitted work. G.B. reports other from Bayer, during the conduct of the study, and other from Vascular Dynamics and Novo Nordisk, outside the submitted work. J.B. reports personal fees from Abbott, grants and personal fees from Abiomed, personal fees from Astra Zeneca, personal fees from Bayer, personal fees from BMS, personal fees from Boehringer Ingelheim, grants and personal fees from CvRX, personal fees from Daiichi Sankyo, personal fees from Medtronic, personal fees from MSD, personal fees from Novartis, personal fees from Pfizer, personal fees from Servier, grants and personal fees from Vifor, and grants and personal fees from Zoll, outside the submitted work. H.H. reports personal fees from Bayer AG, during the conduct of the study, personal fees from Alexion Pharma, from AstraZeneca, and from Vifor Pharma, and personal fees from Böhringer AG, outside the submitted work. T.W. reports grants, personal fees, and other from Kyowa Kirin Co., Ltd, grants and personal fees from Mitsubishi Tanabe Pharma Corporation, grants from Chugai Pharmaceutical Co., Ltd, grants from MSD K.K., personal fees from Bayer Yakuhin Ltd, grants and personal fees from Astellas Pharma Inc., personal fees from AstraZeneca K.K., personal fees from Eli Lilly Japan K.K., personal fees from Ono Pharmaceutical Co., Ltd, grants and personal fees from Kissei Pharmaceutical Co., Ltd, personal fees from Kowa Company, Ltd, grants and personal fees from Sanofi K.K., personal fees from Sanwa Chemistry Co., Ltd, grants and personal fees from Daiichi Sankyo Company, Ltd, personal fees from Taisho Pharma Co., Ltd, grants and personal fees from Takeda Pharmaceutical Company Limited, and personal fees from Nippon Boehringer Ingelheim Co., Ltd, outside the submitted work. F.Z. reports personal fees from Bayer, during the conduct of the study, personal fees from Janssen, personal fees from Novartis, personal fees from Boston Scientific, personal fees from Amgen, personal fees from CVRx, personal fees from Boehringer, other from cardiorenal, personal fees from AstraZeneca, personal fees from Vifor Fresenius, personal fees from Cardior, personal fees from Cereno pharmacuetical, personal fees from Applied Therapeutics, personal fees from Merck, and other from CVCT, outside the submitted work. P.K. is a co-inventor of finerenone (patents EP2132206B1 and US8436180B2) and a full-time employee of Bayer AG.