Selective Mineralocorticoid Receptor Cofactor Modulation as Molecular Basis for Finerenone’s Antifibrotic Activity
Abstract
Mineralocorticoid receptor antagonists (MRAs) reduce morbidity and mortality in chronic heart failure. Novel nonsteroidal MRAs are currently developed and need to be pharmacologically characterized in comparison to classical steroidal MRAs. A mouse model of cardiac fibrosis induced by short-term isoproterenol injection was used to compare the nonsteroidal MRA finerenone and the steroidal MRA eplerenone in equi-efficient systemic MR blocking dosages. Molecular mechanisms were studied in MR-expressing H9C2/MR+ cardiomyocytes and in MR transcriptional cofactor binding assays. Both MRAs significantly inhibited an isoproterenol-mediated increase of left ventricular mass. Isoproterenol-induced cardiac fibrosis and macrophage invasion were potently blocked by finerenone, whereas eplerenone had no significant effect. Speckle tracking echocardiography revealed a significant improvement of global longitudinal peak strain by finerenone, an effect less prominent with eplerenone. Antifibrotic actions of finerenone were accompanied by a significant inhibition of profibrotic cardiac TNX ( tenascin-X ) expression, a regulation absent with eplerenone. Finally, we show a higher potency/efficacy and inverse agonism of finerenone versus eplerenone in MR transcriptional cofactor binding assays indicating differential MR cofactor modulation by steroidal and nonsteroidal MRAs. This study demonstrates that the nonsteroidal MRA finerenone potently prevents cardiac fibrosis and improves strain parameters in mice. Cardiac antifibrotic actions of finerenone may result from the inhibition of profibrotic TNX gene expression mediated by differential MR cofactor binding. Selective MR cofactor modulation provides a molecular basis for distinct (pre)-clinical actions of nonsteroidal and steroidal MRAs.
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Preclinical data showed that the kidney and cardiovascular benefits of finerenone were associated with potent antiinflammatory and antifibrotic effects through inhibition of overactivation of the mineralocorticoid receptor.
“Preclinical data showed that the kidney and cardiovascular benefits of finerenone were associated with potent antiinflammatory and antifibrotic effects through inhibition of overactivation of the mineralocorticoid receptor.6,[10][11][12][13]23”
From Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes (2020) · cites this paper as [10]
The Abstract reports that finerenone blocked cardiac fibrosis and macrophage invasion in mice, and the Discussion describes its cardiac antifibrotic and anti-inflammatory effects. The paper links these findings to mineralocorticoid receptor modulation, but treats a corresponding mechanism for renal benefit as a possibility rather than demonstrating that kidney benefits arise through those same effects. (LLM, conf=0.86)
Experimental — accuracy not yet measuredFinerenone's anti-inflammatory and antifibrotic effects and reduction of urinary albumin-to-creatinine ratio may be related to its benefits in renal outcome and HHF.
“As a nonsteroidal, selective mineralocorticoid receptor antagonist, finerenone has been shown to have potent anti-inflammatory and antifibrotic effects while reducing the urinary albumin-to-creatinine ratio, which may be related to its benefits in renal outcome and HHF [67–70].”
Finerenone has potent anti-inflammatory and antifibrotic effects and reduces the urinary albumin-to-creatinine ratio.
“As a nonsteroidal, selective mineralocorticoid receptor antagonist, finerenone has been shown to have potent anti-inflammatory and antifibrotic effects while reducing the urinary albumin-to-creatinine ratio, which may be related to its benefits in renal outcome and HHF [67–70].”
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Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes
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- Authors
- Grune, J., Beyhoff, N., Smeir, E., Chudek, R., Blumrich, A., Ban, Z., Brix, S., Betz, I. R., Schupp, M., Foryst-Ludwig, A., Klopfleisch, R., Stawowy, P., Houtman, R., Kolkhof, P., & Kintscher, U.
- Affiliations
- Humboldt-Universität zu Berlin (DE)
- From the Department of Medicine/Cardiology, Deutsches Herzzentrum Berlin, Germany (J.G., P.S.); Institute of Pharmacology, Center for Cardiovascular Research, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Germany (J.G., N.B., E.S., R.C., A.B., Z.B., S.B., I.R.B., M.S., A.F.-L., U.K.); DZHK (German Centre for Cardiovascular Research), partner site Berlin (J.G., N.B., E.S., A.B., S.B., I.R.B., A.F.-L....
- ORCID
- Venue
- Hypertension
- Published
- 2018-04
- Volume
- 71
- Issue
- 4
- Pages
- 599-608
- ISSN
- 0194-911X (ISSN-L)
- 1524-4563
- OpenAlex
- W2883307844
- Cited by
- 292
- References
- 30
- Citations by year
- 2026: 51 · 2025: 45 · 2024: 37 · 2023: 50 · 2022: 53 · 2021: 26 · 2020: 15 · 2019: 12 · 2018: 2
- FWCI
- 10.39
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Hypertension (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Heart Association
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal Regulation and Hypertension
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
- Keywords
- finerenone, eplerenone, mineralocorticoid receptor antagonists, myocardial fibrosis, antifibrotic activity, tenascin-X, macrophage infiltration, left ventricular mass, cardiomyocytes, inverse agonism, chronic heart failure
- MeSH terms
- Eplerenone, Mineralocorticoid Receptor Antagonists, Animals, Biological Availability, Disease Models, Animal, Gene Expression Regulation, Heart Failure, Naphthyridines, Tenascin, Myocytes, Cardiac, Mice
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