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2016 ; 11
(8
): e0161760
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Diminazene Aceturate Improves Cardiac Fibrosis and Diastolic Dysfunction in Rats
with Kidney Disease
#MMPMID27571511
Velkoska E
; Patel SK
; Griggs K
; Burrell LM
PLoS One
2016[]; 11
(8
): e0161760
PMID27571511
show ga
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.
|Angiotensin-Converting Enzyme 2
[MESH]
|Animals
[MESH]
|Blood Pressure/drug effects
[MESH]
|Diminazene/*analogs & derivatives/therapeutic use
[MESH]