Abstract: FR-PO998
The Nonsteroidal Mineralocorticoid Receptor Antagonist Finerenone Improves Left Ventricular Function in Preclinical CKD
Session Information
- CKD Mechanisms: From Mendel to Mars
November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2303 CKD (Non-Dialysis): Mechanisms
Authors
- Jaisser, Frederic, INSERM, UMRS 1138, Centre de Recherche des Cordeliers, Sorbonne Université, Université Paris Cité, Paris, Select State, France
- Lima Posada, Ixchel Quetzaliztli, INSERM, UMRS 1138, Centre de Recherche des Cordeliers, Sorbonne Université, Université Paris Cité, Paris, Select State, France
- Stephan, Yohan, Univ Rouen Normandie, INSERM EnVI UMR 1096, Rouen, France
- Soulié, Matthieu, INSERM, UMRS 1138, Centre de Recherche des Cordeliers, Sorbonne Université, Université Paris Cité, Paris, Select State, France
- Palacios Ramirez, Roberto, INSERM, UMRS 1138, Centre de Recherche des Cordeliers, Sorbonne Université, Université Paris Cité, Paris, Select State, France
- Bonnard, Benjamin, INSERM, UMRS 1138, Centre de Recherche des Cordeliers, Sorbonne Université, Université Paris Cité, Paris, Select State, France
- Nicol, Lionel, Univ Rouen Normandie, INSERM EnVI UMR 1096, Rouen, France
- Kolkhof, Peter, Cardiovascular Precision Medicines, Research and Early Development, Pharmaceuticals, Bayer AG, Wuppertal, Germany
- Mulder, Paul, Univ Rouen Normandie, INSERM EnVI UMR 1096, Rouen, France
Group or Team Name
- Diabetes, metabolic diseases and comorbidities
Background
The mineralocorticoid receptor (MR) plays an important role in the development of CKD and associated cardiovascular complications. Antagonizing the overactivation of the MR with MR antagonists (MRA) is a therapeutic option. Finerenone is a novel non-steroidal MRA that has been recently studied in two large clinical trials showing the beneficial effects in stage 1 to 4 CKD patients with type 2 diabetes (T2D) in the FIDELIO-DKD and FIGARO-DKD trials.
Aim: To test whether finerenone improves renal/cardiac functions in preclinical non-diabetic CKD.
Methods
CKD was induced by 5/6 nephrectomy in 6 weeks old Sprague Dawley rats. Finerenone (10 mg/kg/day) was administered as curative treatment (1 month after 5/6 nephrectomy). Left Ventricle (LV) function/hemodynamics, LV tissue perfusion and GFR were assessed in vivo at the age of 24 weeks. Cardiac fibrosis was estimated by Sirius red staining and activation of eNOS (peNOS ser 1177) in the heart was estimated by western-blot analysis.
Results
12 weeks after 5/6 nephrectomy, the rats showed classical signs of CKD: reduced GFR and increased kidney weight; associated with LV diastolic dysfunction: increased in LV end-diastolic pressure (LVEDP), LV relaxation constant (Tau) and LV end-diastolic pressure volume-relation (LVEDPVR), while LV perfusion was reduced. Changes associated with increased cardiac fibrosis and reduced peNOS ser 1177. Curative treatment with finerenone reduced significantly both LVEDPVR and Tau; and increased LV tissue perfusion, associated with a reduction in cardiac fibrosis and increased eNOS phosphorylation. Finerenone treatment did not impact GFR but reduced renal hypertrophy.
Conclusion
Curative treatment with finerenone improves non-diabetic CKD related LV diastolic function, associated with a reduction of cardiac fibrosis, and increased cardiac eNOS activating phosphorylation (ser 1177) independently from changes in kidney function.
Funding
- Commercial Support – Bayer-AG