Diminazene Aceturate Improves Cardiac Fibrosis and Diastolic Dysfunction in Rats with Kidney Disease.

Elena Velkoska,Louise M Burrell,Sheila K Patel,Karen Griggs

doi:10.1371/journal.pone.0161760

Elena Velkoska, Louise M Burrell + Show 2 more

Open Access

https://doi.org/10.1371/journal.pone.0161760

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Journal: PloS one	Publication Date: Aug 29, 2016
Citations: 52	License type: CC BY 4.0

Affiliation: Austin Health, University of Melbourne

Abstract

Angiotensin converting enzyme (ACE) 2 is a negative regulator of the renin angiotensin system (RAS) through its role to degrade angiotensin II. In rats with subtotal nephrectomy (STNx), adverse cardiac remodelling occurs despite elevated cardiac ACE2 activity. We hypothesised that diminazene aceturate (DIZE), which has been described as having an off-target effect to activate ACE2, would have beneficial cardiac effects in STNx rats. STNx led to hypertension, diastolic dysfunction, left ventricular hypertrophy, cardiac fibrosis, and increased cardiac ACE, ACE2, Ang II and Ang 1–7 levels. Cardiac gene expression of ADAM17 was also increased. In STNx, two-weeks of subcutaneous DIZE (15mg/kg/d) had no effect on blood pressure but improved diastolic dysfunction and cardiac fibrosis, reduced ADAM17 mRNA and shifted the cardiac RAS balance to a cardioprotective profile with reduced ACE and Ang II. There was no change in cardiac ACE2 activity or in cardiac Ang 1–7 levels with DIZE. In conclusion, our results suggest that DIZE exerts a protective effect on the heart under the pathological condition of kidney injury. This effect was not due to improved kidney function, a fall in blood pressure or a reduction in LVH but was associated with a reduction in cardiac ACE and cardiac Ang II levels. As in vitro studies showed no direct effect of DIZE on ACE2 or ACE activity, the precise mechanism of action of DIZE remains to be determined.

Highlights

The prevalence of kidney disease is increasing worldwide and cardiovascular disease is the major cause of morbidity and mortality [1, 2]
We explored the role of ACE2 in the cardiac consequences of kidney disease using a model of kidney injury due to STNx
We report that STNx rats had increased cardiac Ang II and Ang 1–7 levels and increased cardiac gene expression of ADAM17

Summary

Introduction

The prevalence of kidney disease is increasing worldwide and cardiovascular disease is the major cause of morbidity and mortality [1, 2]. In kidney disease secondary to subtotal nephrectomy (STNx), kidney ACE and Ang II are increased [9,10,11,12,13] and kidney ACE2 activity is decreased [12, 14] These findings have led to strategies to replenish ACE2 using recombinant ACE2 or to activate ACE2 using compounds such as diminazene aceturate (DIZE) [15]. The focus of this paper was to investigate the effect of short-term DIZE on cardiac structure and function, cardiac ACE/ACE2 gene expression/activity and cardiac angiotensin peptide (Ang II/Ang 1–7) levels in STNx rats with an activated RAS and in Control rats with a balanced RAS. We assessed gene expression of cardiac ADAM17 [21], a proteinase that is responsible for the cleavage or “shedding” of the catalytically active ectodomain of ACE2 from the cell membrane

Materials and Methods

Results

Discussion