title: Short-term treatment with diminazene aceturate ameliorates the reduction in kidney ACE2 activity in rats with subtotal nephrectomy.
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.
authors.affiliation: Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, Victoria, Australia.
authors.forename: Elena
authors.initials: E
authors.lastname: Velkoska
authors.affiliation: Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, Victoria, Australia.
authors.forename: Sheila K
authors.initials: SK
authors.lastname: Patel
authors.affiliation: Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, Victoria, Australia.
authors.forename: Karen
authors.initials: K
authors.lastname: Griggs
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
authors.forename: Raelene J
authors.initials: RJ
authors.lastname: Pickering
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
authors.forename: Chris
authors.initials: C
authors.lastname: Tikellis
authors.affiliation: Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, Victoria, Australia.
authors.forename: Louise M
authors.initials: LM
authors.lastname: Burrell
mesh_terms: D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D004133:Diminazene / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology* / Q000293:injuries / Q000502:physiology; D007672:Kidney Cortex / Q000187:drug effects / Q000201:enzymology; D007679:Kidney Medulla / Q000187:drug effects / Q000201:enzymology; D009392:Nephrectomy / Q000009:adverse effects*; D007703:Peptidyl-Dipeptidase A / Q000097:blood / Q000235:genetics / Q000378:metabolism* / Q000652:urine; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
chemical_list: D012333:RNA, Messenger; D007703:Peptidyl-Dipeptidase A; C000705329:Ace2 protein, rat; D000085962:Angiotensin-Converting Enzyme 2; C003915:diminazene aceturate; D004133:Diminazene