Comparison of the antiremodeling effects of losartan and mirabegron in a rat model of uremic cardiomyopathy

Zsuzsanna Z A Kovács,Ferenc Kovács,Bálint Gábor Cserni,Tamás Csont,Fanni M Márványkövi,Mónika G Kovács,Bence Kővári,Andrea Siska,Hoa Dinh,Marah Freiwan,Gergő Szűcs,Imre Földesi,Katalin Farkas,Márta Sárközy,Gábor Cserni,András Kriston,Péter Horváth

doi:10.1038/s41598-021-96815-5

Abstract

Uremic cardiomyopathy is characterized by diastolic dysfunction (DD), left ventricular hypertrophy (LVH), and fibrosis. Angiotensin-II plays a major role in the development of uremic cardiomyopathy via nitro-oxidative and inflammatory mechanisms. In heart failure, the beta-3 adrenergic receptor (β3-AR) is up-regulated and coupled to endothelial nitric oxide synthase (eNOS)-mediated pathways, exerting antiremodeling effects. We aimed to compare the antiremodeling effects of the angiotensin-II receptor blocker losartan and the β3-AR agonist mirabegron in uremic cardiomyopathy. Chronic kidney disease (CKD) was induced by 5/6th nephrectomy in male Wistar rats. Five weeks later, rats were randomized into four groups: (1) sham-operated, (2) CKD, (3) losartan-treated (10 mg/kg/day) CKD, and (4) mirabegron-treated (10 mg/kg/day) CKD groups. At week 13, echocardiographic, histologic, laboratory, qRT-PCR, and Western blot measurements proved the development of uremic cardiomyopathy with DD, LVH, fibrosis, inflammation, and reduced eNOS levels, which were significantly ameliorated by losartan. However, mirabegron showed a tendency to decrease DD and fibrosis; but eNOS expression remained reduced. In uremic cardiomyopathy, β3-AR, sarcoplasmic reticulum ATPase (SERCA), and phospholamban levels did not change irrespective of treatments. Mirabegron reduced the angiotensin-II receptor 1 expression in uremic cardiomyopathy that might explain its mild antiremodeling effects despite the unchanged expression of the β3-AR.

Highlights

Uremic cardiomyopathy is characterized by diastolic dysfunction (DD), left ventricular hypertrophy (LVH), and fibrosis
Serum carbamide and creatinine levels were significantly increased in the 5/6th nephrectomized groups irrespective of losartan or mirabegron treatment compared to the sham-operated group at weeks 4 and 13, respectively (Fig. 2a,b)
In the 5/6th nephrectomized rats, uremic cardiomyopathy developed with similar laboratory and cardiac alterations to those in Chronic kidney disease (CKD)-induced heart failure with preserved ejection fraction (HFpEF) patients

Summary

Introduction

Uremic cardiomyopathy is characterized by diastolic dysfunction (DD), left ventricular hypertrophy (LVH), and fibrosis. The CKD-associated chronic structural, functional, and electrophysiological remodeling of the heart is called uremic cardiomyopathy (i.e., type 4 cardiorenal syndrome)[4,5] It is characterized by diastolic dysfunction (DD), left ventricular hypertrophy (LVH), capillary rarefaction, endothelial dysfunction, and fibrosis in the stage of heart failure with preserved ejection fraction (HFpEF)[5,6]. Belge et al demonstrated that angiotensin-II administration did not induce cardiac fibrosis and hypertrophy in mice with cardiomyocyte-specific expression of human β3-AR22 It has been described in pancreatic[23] and lung tissues[24] of male apoE knock-out mice that chronic administration of the β3-AR agonist BRL37344 could down-regulate the AT1 receptors. Our present study aimed to compare the antiremodeling effects of the ARB losartan used in standard heart failure therapy and the novel β3-AR agonist mirabegron in uremic cardiomyopathy in rats

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