Cargando…
Nonsteroidal Mineralocorticoid Receptor Antagonism by Finerenone—Translational Aspects and Clinical Perspectives across Multiple Organ Systems
Perception of the role of the aldosterone/mineralocorticoid receptor (MR) ensemble has been extended from a previously renal epithelial-centered focus on sodium and volume homeostasis to an understanding of their role as systemic modulators of reactive oxygen species, inflammation, and fibrosis. Ste...
Autores principales: | , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9408839/ https://www.ncbi.nlm.nih.gov/pubmed/36012508 http://dx.doi.org/10.3390/ijms23169243 |
_version_ | 1784774700337987584 |
---|---|
author | Kolkhof, Peter Lawatscheck, Robert Filippatos, Gerasimos Bakris, George L. |
author_facet | Kolkhof, Peter Lawatscheck, Robert Filippatos, Gerasimos Bakris, George L. |
author_sort | Kolkhof, Peter |
collection | PubMed |
description | Perception of the role of the aldosterone/mineralocorticoid receptor (MR) ensemble has been extended from a previously renal epithelial-centered focus on sodium and volume homeostasis to an understanding of their role as systemic modulators of reactive oxygen species, inflammation, and fibrosis. Steroidal MR antagonists (MRAs) are included in treatment paradigms for resistant hypertension and heart failure with reduced ejection fraction, while more recently, the nonsteroidal MRA finerenone was shown to reduce renal and cardiovascular outcomes in two large phase III trials (FIDELIO-DKD and FIGARO-DKD) in patients with chronic kidney disease and type 2 diabetes, respectively. Here, we provide an overview of the pathophysiologic role of MR overactivation and preclinical evidence with the nonsteroidal MRA finerenone in a range of different disease models with respect to major components of the aggregate mode of action, including interfering with reactive oxygen species generation, inflammation, fibrosis, and hypertrophy. We describe a time-dependent effect of these mechanistic components and the potential modification of major clinical parameters, as well as the impact on clinical renal and cardiovascular outcomes as observed in FIDELIO-DKD and FIGARO-DKD. Finally, we provide an outlook on potential future clinical indications and ongoing clinical studies with finerenone, including a combination study with a sodium–glucose cotransporter-2 inhibitor. |
format | Online Article Text |
id | pubmed-9408839 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-94088392022-08-26 Nonsteroidal Mineralocorticoid Receptor Antagonism by Finerenone—Translational Aspects and Clinical Perspectives across Multiple Organ Systems Kolkhof, Peter Lawatscheck, Robert Filippatos, Gerasimos Bakris, George L. Int J Mol Sci Review Perception of the role of the aldosterone/mineralocorticoid receptor (MR) ensemble has been extended from a previously renal epithelial-centered focus on sodium and volume homeostasis to an understanding of their role as systemic modulators of reactive oxygen species, inflammation, and fibrosis. Steroidal MR antagonists (MRAs) are included in treatment paradigms for resistant hypertension and heart failure with reduced ejection fraction, while more recently, the nonsteroidal MRA finerenone was shown to reduce renal and cardiovascular outcomes in two large phase III trials (FIDELIO-DKD and FIGARO-DKD) in patients with chronic kidney disease and type 2 diabetes, respectively. Here, we provide an overview of the pathophysiologic role of MR overactivation and preclinical evidence with the nonsteroidal MRA finerenone in a range of different disease models with respect to major components of the aggregate mode of action, including interfering with reactive oxygen species generation, inflammation, fibrosis, and hypertrophy. We describe a time-dependent effect of these mechanistic components and the potential modification of major clinical parameters, as well as the impact on clinical renal and cardiovascular outcomes as observed in FIDELIO-DKD and FIGARO-DKD. Finally, we provide an outlook on potential future clinical indications and ongoing clinical studies with finerenone, including a combination study with a sodium–glucose cotransporter-2 inhibitor. MDPI 2022-08-17 /pmc/articles/PMC9408839/ /pubmed/36012508 http://dx.doi.org/10.3390/ijms23169243 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Review Kolkhof, Peter Lawatscheck, Robert Filippatos, Gerasimos Bakris, George L. Nonsteroidal Mineralocorticoid Receptor Antagonism by Finerenone—Translational Aspects and Clinical Perspectives across Multiple Organ Systems |
title | Nonsteroidal Mineralocorticoid Receptor Antagonism by Finerenone—Translational Aspects and Clinical Perspectives across Multiple Organ Systems |
title_full | Nonsteroidal Mineralocorticoid Receptor Antagonism by Finerenone—Translational Aspects and Clinical Perspectives across Multiple Organ Systems |
title_fullStr | Nonsteroidal Mineralocorticoid Receptor Antagonism by Finerenone—Translational Aspects and Clinical Perspectives across Multiple Organ Systems |
title_full_unstemmed | Nonsteroidal Mineralocorticoid Receptor Antagonism by Finerenone—Translational Aspects and Clinical Perspectives across Multiple Organ Systems |
title_short | Nonsteroidal Mineralocorticoid Receptor Antagonism by Finerenone—Translational Aspects and Clinical Perspectives across Multiple Organ Systems |
title_sort | nonsteroidal mineralocorticoid receptor antagonism by finerenone—translational aspects and clinical perspectives across multiple organ systems |
topic | Review |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9408839/ https://www.ncbi.nlm.nih.gov/pubmed/36012508 http://dx.doi.org/10.3390/ijms23169243 |
work_keys_str_mv | AT kolkhofpeter nonsteroidalmineralocorticoidreceptorantagonismbyfinerenonetranslationalaspectsandclinicalperspectivesacrossmultipleorgansystems AT lawatscheckrobert nonsteroidalmineralocorticoidreceptorantagonismbyfinerenonetranslationalaspectsandclinicalperspectivesacrossmultipleorgansystems AT filippatosgerasimos nonsteroidalmineralocorticoidreceptorantagonismbyfinerenonetranslationalaspectsandclinicalperspectivesacrossmultipleorgansystems AT bakrisgeorgel nonsteroidalmineralocorticoidreceptorantagonismbyfinerenonetranslationalaspectsandclinicalperspectivesacrossmultipleorgansystems |