Mineralocorticoid receptor (MR) antagonist eplerenone and MR modulator balcinrenone prevent renal extracellular matrix remodeling and inflammation via the MR/proteoglycan/TLR4 pathway

Author:

Palacios-Ramirez Roberto1ORCID,Soulié Matthieu1,Fernandez-Celis Amaya2,Nakamura Toshifumi1,Boujardine Nabiha1,Bonnard Benjamin1,Bamberg Krister3,Lopez-Andres Natalia2ORCID,Jaisser Frederic14ORCID

Affiliation:

1. 1Centre de Recherche des Cordeliers, Team Diabetes, Metabolic Diseases and Comorbidities, Sorbonne Université, Inserm, Université de Paris, Paris, France

2. 2Cardiovascular Translational Research, Navarrabiomed (Miguel Servet Foundation), Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain

3. 3Early Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden

4. 4Université de Lorraine, INSERM Centre d'Investigations Cliniques-Plurithématique 1433, UMR 1116, CHRU de Nancy, French-Clinical Research Infrastructure Network (F-CRIN) INI-CRCT, Nancy, France

Abstract

Abstract Excessive activation of the mineralocorticoid receptor (MR) is implicated in cardiovascular and renal disease. Decreasing MR activation with MR antagonists (MRA) is effective to slow chronic kidney disease (CKD) progression and its cardiovascular comorbidities in animal models and patients. The present study evaluates the effects of the MR modulator balcinrenone and the MRA eplerenone on kidney damage in a metabolic CKD mouse model combining nephron reduction and a 60% high-fat diet. Balcinrenone and eplerenone prevented the progression of renal damages, extracellular matrix remodeling and inflammation to a similar extent. We identified a novel mechanism linking MR activation to the renal proteoglycan deposition and inflammation via the TLR4 pathway activation. Balcinrenone and eplerenone similarly blunted this pathway activation.

Funder

Agence Nationale de la Recherche

Institut National de la Santé et de la Recherche Médicale

Publisher

Portland Press Ltd.

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