Short-term treatment with diminazene aceturate ameliorates the reduction in kidney ACE2 activity in rats with subtotal nephrectomy.

Elena Velkoska,Raelene J Pickering,Louise M Burrell,Sheila K Patel,Chris Tikellis,Karen Griggs,Michael Bader

doi:10.1371/journal.pone.0118758

Elena Velkoska, Raelene J Pickering + Show 5 more

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https://doi.org/10.1371/journal.pone.0118758

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Abstract

Angiotensin converting enzyme (ACE) 2 is an important modulator of the renin angiotensin system (RAS) through its role to degrade angiotensin (Ang) II. Depletion of kidney ACE2 occurs following kidney injury due to renal mass reduction and may contribute to progressive kidney disease. This study assessed the effect of diminazine aceturate (DIZE), which has been described as an ACE2 activator, on kidney ACE2 mRNA and activity in rats with kidney injury due to subtotal nephrectomy (STNx). Sprague Dawley rats were divided into Control groups or underwent STNx; rats then received vehicle or the DIZE (s.c. 15 mg/kg/day) for 2 weeks. STNx led to hypertension (P<0.01), kidney hypertrophy (P<0.001) and impaired kidney function (P<0.001) compared to Control rats. STNx was associated with increased kidney cortical ACE activity, and reduced ACE2 mRNA in the cortex (P<0.01), with reduced cortical and medullary ACE2 activity (P<0.05), and increased urinary ACE2 excretion (P<0.05) compared to Control rats. Urinary ACE2 activity correlated positively with urinary protein excretion (P<0.001), and negatively with creatinine clearance (P=0.04). In STNx rats, DIZE had no effect on blood pressure or kidney function, but was associated with reduced cortical ACE activity (P<0.01), increased cortical ACE2 mRNA (P<0.05) and increased cortical and medullary ACE2 activity (P<0.05). The precise in vivo mechanism of action of DIZE is not clear, and its effects to increase ACE2 activity may be secondary to an increase in ACE2 mRNA abundance. In ex vivo studies, DIZE did not increase ACE2 activity in either Control or STNx kidney cortical membranes. It is not yet known if chronic administration of DIZE has long-term benefits to slow the progression of kidney disease.

Highlights

Kidney disease is increasing in prevalence and incidence, and is associated with considerable morbidity and mortality [1]
The importance of the level of ACE2 expression in kidney disease causality come from studies of ACE2 inhibition, which worsened glomerular injury in a mouse model of type 1 diabetes [9], presumably due to the removal of a degradative pathway for Ang II, and from ACE2 gene knockout mice (KO) with type 1 diabetes, where accelerated kidney injury was ameliorated by angiotensin type 1 receptor (AT1R) blockade [10]
In STNx rats, diminazine aceturate (DIZE) had no effect on blood pressure or kidney function but decreased cortical angiotensin converting enzyme (ACE) activity, and ameliorated the reduction in kidney ACE2 activity

Summary

Introduction

Kidney disease is increasing in prevalence and incidence, and is associated with considerable morbidity and mortality [1]. Effect of DIZE in Subtotal Nephrectomy major role in the progression of kidney disease, and blockade of the classic arm of the RAS is recommended as first line therapy [2]. Taken together the data suggests that imbalance in the tissue RAS with upregulation of the deleterious ACE/Ang II pathway and loss of the protective ACE2/Ang 1–7 pathway may predispose to the development and progression of kidney disease. This concept has led to strategies to replenish ACE2 or to activate ACE2 [18]

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