title: Diminazene Aceturate Improves Cardiac Fibrosis and Diastolic Dysfunction in Rats with Kidney Disease.
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.
authors: Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, Victoria, Australia.
authors: Elena
authors: E
authors: Velkoska
authors: Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, Victoria, Australia.
authors: Sheila K
authors: SK
authors: Patel
authors: Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, Victoria, Australia.
authors: Karen
authors: K
authors: Griggs
authors: Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, Victoria, Australia.
authors: Louise M
authors: http://orcid.org/0000-0003-1863-7539
authors: LM
authors: Burrell
mesh_terms: D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004133:Diminazene / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005260:Female; D005355:Fibrosis / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D006973:Hypertension / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D017379:Hypertrophy, Left Ventricular / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D007674:Kidney Diseases / Q000150:complications*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology*; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D007703:Peptidyl-Dipeptidase A; C000705329:Ace2 protein, rat; D000085962:Angiotensin-Converting Enzyme 2; C003915:diminazene aceturate; D004133:Diminazene