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Comparative Study
. 2021 Sep 1;11(1):17495.
doi: 10.1038/s41598-021-96815-5.

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

Zsuzsanna Z A Kovács  1 , Gergő Szűcs  1 , Marah Freiwan  1 , Mónika G Kovács  1 , Fanni M Márványkövi  1 , Hoa Dinh  1 , Andrea Siska  2 , Katalin Farkas  2 , Ferenc Kovács  3   4 , András Kriston  3   4 , Péter Horváth  3   4   5 , Bence Kővári  6 , Bálint Gábor Cserni  6 , Gábor Cserni  6 , Imre Földesi  2 , Tamás Csont  7 , Márta Sárközy  8
Affiliations
Comparative Study

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

Zsuzsanna Z A Kovács et al. Sci Rep. .

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.

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Conflict of interest statement

Single-Cell Technologies Ltd., Hungary, developed the Biology Image Analysis Software (BIAS). P.H. is the CEO, A.K. is a software architect, and F. K is a software engineer at Single-Cell Technologies Ltd.

Figures

Figure 1
Figure 1
Experimental setup. BP blood pressure, CKD chronic kidney disease, LV left ventricle, OP operation, WB Western blot.
Figure 2
Figure 2
The effects of losartan and mirabegron on the development of CKD in 5/6th nephrectomized rats. (a) Serum carbamide concentration, (b) serum creatinine concentration, (c) creatinine clearance, (d) urine creatinine concentration, (e) urine volume, and (f) urine protein concentration at week 4 and the endpoint. Values are presented as mean ± S.E.M., *p < 0.05 vs. sham-operated group and #p < 0.05 vs. CKD group (n = 7–10, One-Way ANOVA, Holm-Sidak post hoc test), $p < 0.05 vs. week 4 in the same group (n = 7–10, Two-ways repeated-measures ANOVA, Holm-Sidak post hoc test). Sham sham-operated group, CKD chronic kidney disease group, CKD + L losartan-treated chronic kidney disease group, CKD + M mirabegron-treated chronic kidney disease group. Creatinine clearance was calculated according to the standard formula (urine creatinine concentration [μM] × urine volume for 24 h [mL])/(serum creatinine concentration [μM] × 24 × 60 min). †At the endpoint, urine volume and creatinine concentration were measured at week 12 and serum creatinine concentration at week 13.
Figure 3
Figure 3
The effects of losartan and mirabegron on the echocardiographic parameters at week 13. (a) Representative M-mode images, (b) ejection fraction (EF), (c) diastolic septal mitral annulus velocity (e'), (d) posterior wall thicknesses in systole (PWTs) and (e) diastole (PWTd), (f) septal wall thickness in systole (SWTs) and (g) diastole (SWTd). Values are presented as mean ± S.E.M., *p < 0.05 vs. sham-operated group, #p < 0.05 vs. CKD group (n = 7–10, One-Way ANOVA, Holm-Sidak post hoc test), $p < 0.05 vs. week 4 in the same group (n = 7–10, Two-ways repeated-measures ANOVA, Holm-Sidak post hoc test). Sham sham-operated group, CKD chronic kidney disease group, CKD + L losartan-treated chronic kidney disease group, CKD + M mirabegron-treated chronic kidney disease group. Representative M-mode images were saved from the EchoPac Dimension v201 software.
Figure 4
Figure 4
The effects of losartan and mirabegron on left ventricular hypertrophy and fibrosis assessed by histology at week 13. (a) Representative haematoxylin–eosin (HE)-stained slides at 100 × and (c) 40 × magnification, (b) cardiomyocyte diameters and (d) cross-sectional areas, (e) representative picrosirius red and fast green (PSFG)-stained slides at 20 × magnification, (f) left ventricular collagen content. On the digital HE images, cardiomyocyte diameters and cross-sectional areas were measured in 100 selected cardiomyocytes on left ventricular sections cut on the same plane. The mean values of the collagen content of 10 representative PSFG-stained images were calculated and used for statistical evaluation in the case of each left ventricular slide. Scale bars represent 20 µm at the 100 × magnified images, 50 µm at the 40 × magnified images, and 100 µm at the 20 × magnified images. Values are presented as mean ± S.E.M., *p < 0.05 vs. sham-operated group, #p < 0.05 vs. CKD group. (n = 7–10, One-Way ANOVA, Holm-Sidak post hoc test). Sham sham-operated group, CKD chronic kidney disease group, CKD + L losartan-treated chronic kidney disease group, CKD + M mirabegron-treated chronic kidney disease group. Representative HE- or PSFG-stained slides were captured in the Panoramic Viewer 1.15.4 software.
Figure 5
Figure 5
The effects of losartan and mirabegron on the protein expression at week 13 assessed by Western blot. Left ventricular expression and cropped representative images of (a) beta-3 adrenergic receptor (β3-AR), (b) endothelial nitric oxide synthase (eNOS), (c) phospho-eNOS, (d) phospho-eNOS/ eNOS ratio, (e) sarcoendoplasmic reticulum calcium ATPase 2a (SERCA2a), (f) phospholamban (PLN), (g) phospho-PLN (pPLN), and (h) phospho-PLN/PLN ratio. Values are presented as mean ± S.E.M., *p < 0.05 vs. sham-operated group, #p < 0.05 vs. CKD group (n = 6–7, One-Way ANOVA, Holm-Sidak post hoc test). Sham sham-operated group, CKD chronic kidney disease group, CKD + L losartan-treated chronic kidney disease group, CKD + M mirabegron-treated chronic kidney disease group. Images were captured with the Odyssey CLx machine and exported with Image Studio 5.2.5 software. The full-length Western blots are presented in Supplementary Figures S1-12.
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References

    1. Romagnani P, et al. Chronic kidney disease. Nat. Rev. Dis. Prim. 2017;3:1–24. - PubMed
    1. Bikbov B, et al. Global, regional, and national burden of chronic kidney disease, 1990–2017: A systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2020;395:709–733. doi: 10.1016/S0140-6736(20)30045-3. - DOI - PMC - PubMed
    1. Duni A, Liakopoulos V, Rapsomanikis KP, Dounousi E. Chronic kidney disease and disproportionally increased cardiovascular damage: Does oxidative stress explain the burden? Oxid. Med. Cell. Longev. 2017;2017:2. doi: 10.1155/2017/9036450. - DOI - PMC - PubMed
    1. Samoni S, Husain-Syed F, De Rosa S, Ronco C. Cardio-pulmonary–renal interactions. G. Ital. Nefrol. 2017;34:162–177. - PubMed
    1. Wang X, Shapiro JI. Evolving concepts in the pathogenesis of uraemic cardiomyopathy. Nat. Rev. Nephrol. 2019;15:159–175. doi: 10.1038/s41581-018-0101-8. - DOI - PubMed

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