Mineralocorticoid receptor antagonism improves diastolic dysfunction in chronic kidney disease in mice

• Published in: Journal of molecular and cellular cardiology Vol. 121; pp. 124 - 133
• Main Authors: Bonnard, Benjamin, Pieronne-Deperrois, Marie, Djerada, Zoubir, Elmoghrabi, Soumaya, Kolkhof, Peter, Ouvrard-Pascaud, Antoine, Mulder, Paul, Jaisser, Frédéric, Messaoudi, Smail
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-08-2018; Elsevier
• Subjects: Animal biology; Cardio-renal syndrome; Diastolic dysfunction; Finerenone; Human health and pathology; Life Sciences; Mineralocorticoid receptor; Cardio-renal syndrome; Diastolic dysfunction; Mineralocorticoid receptor; Finerenone
• ISSN: 0022-2828; 1095-8584
• DOI: 10.1016/j.yjmcc.2018.06.008

Managing the cardiovascular complications of renal failure is a major therapeutic challenge in clinical practice. Mineralocorticoid Receptor (MR) blockade is a highly effective strategy for the management of heart failure, but the use of MR antagonists (MRA) is limited by their side effects rendering them contraindicated in patients with renal failure. Finerenone is a new non-steroidal MRA that shows fewer hyperkaliaemic events than the traditional steroidal MRAs and could therefore represent an alternative to these molecules in patients with damaged kidney function. The aim of this study is to characterize the effects of Finerenone on the cardiac complications of renal failure in a mouse model of chronic kidney disease (CKD). CKD was induced by subtotal nephrectomy (Nx), and finerenone was administered at a low dose (2.5 mg/kg/d) from week 4 to week 10 post-Nx. Cardiac function was assessed by echocardiography and invasive hemodynamics while cardiac fibrosis was measured by Sirius Red staining. Renal failure induced cardiac systolic and diastolic dysfunctions in the untreated CKD mice, as well as minor changes on cardiac structure. We also observed alterations in the phosphorylation of proteins playing key roles in the calcium handling (Phospholamban, Calmodulin kinase II) in these mice. Finerenone prevented most of these lesions with no effects on neither the renal dysfunction nor kaliemia. The benefits of finerenone suggest that activation of MR is involved in the cardiac complication of renal failure and strengthen previous studies showing beneficial effects of MRA in patients with CKD.
•MR antagonism improves renal failure-induced cardiac diastolic dysfunction in mice.•This is associated with an improvement in cardiac Ca + handling proteins activation.•These effects are independent of an improvement in renal function.