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Published on: February 17, 2018
(Pro)renin Receptor Blockade Ameliorates Heart Failure Caused by Chronic Kidney Disease
Akihiro Yoshida1, Hiromitsu Kanamori1, Genki Naruse1
1Department of Cardiology, Gifu University Graduate School of Medicine, Gifu, Japan.
Insights
Blocking the (pro)renin receptor with handle-region peptide (HRP) effectively treats chronic kidney disease-associated heart failure by reducing cardiac fibrosis and hypertrophy.
Area of Science:
- Cardiovascular Research
- Nephrology
- Pharmacology
Background:
- The (pro)renin receptor [(P)RR] plays a key role in activating the local renin-angiotensin system, contributing to cardiovascular disease.
- Chronic kidney disease (CKD) is frequently associated with heart failure, necessitating therapeutic strategies.
Purpose of the Study:
- To investigate the therapeutic potential of a (P)RR blocker, handle-region peptide (HRP), in mitigating heart failure associated with CKD.
- To evaluate the effects of HRP on cardiac structure and function in a mouse model of CKD.
Main Methods:
- CKD was induced in mice via five-sixths nephrectomy.
- Mice with established cardiac dysfunction and hypertension were treated with vehicle, low-dose HRP, or high-dose HRP for 4 weeks.
Main Results:
- High-dose HRP treatment significantly improved cardiac function, reversed left ventricular dilation, and ameliorated hypertension.
- HRP administration attenuated cardiac fibrosis, cardiomyocyte hypertrophy, macrophage infiltration, and oxidative DNA damage.
- Myocardial expression of Ang II, AT1R, TGF-β1, ECM proteins, and lipid peroxidation was reduced by HRP; cardiomyocyte autophagy was unaffected.
Conclusions:
- Blockade of the (P)RR using HRP is a promising therapeutic strategy for managing CKD-associated heart failure.
- HRP effectively suppresses cardiac fibrosis and hypertrophy, offering a beneficial approach to ameliorate heart failure in the context of CKD.
Background:
The (pro)renin receptor [(P)RR)] is involved in the activation of local renin-angiotensin system and subsequent development of cardiovascular disease. We investigated the therapeutic effect of a (P)RR blocker, handle-region peptide (HRP), on chronic kidney disease (CKD)-associated heart failure.
Methods And Results:
CKD was induced in C57BL/6J mice by means of five-sixths nephrectomy. Eight weeks later, cardiac dysfunction and cardiac dilatation with hypertension developed. Mice were then assigned to 1 of the 3 following groups: vehicle, low-dose (0.01 mg·kg-1·d-1) HRP, or high-dose (0.3 mg·kg-1·d-1) HRP for 4 weeks. High-dose HRP treatment reversed left ventricular dilation and significantly improved cardiac dysfunction with ameliorated hypertension compared with the vehicle. The hearts with high-dose HRP treatment showed significant attenuation of cardiac fibrosis, cardiomyocyte hypertrophy, macrophage infiltration, and oxidative DNA damage. This treatment decreased the myocardial expressions of angiotensin (Ang) II, Ang II type 1 receptor, transforming growth factor β1, extracellular matrix-related proteins, and lipid peroxidation. Autophagy was activated in the cardiomyocyte from nephrectomized mice, but HRP treatment had no effect on cardiomyocyte autophagy.
Conclusions:
This study indicates that (P)PR blockade is a beneficial strategy by suppressing cardiac fibrosis and hypertrophy to ameliorate heart failure caused by CKD.
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