Acute kidney injury in the rat causes cardiac remodelling and increases angiotensin-converting enzyme 2 expression.
Patients with kidney failure are at high risk of a cardiac death and frequently develop left ventricular hypertrophy (LVH). The mechanisms involved in the cardiac structural changes that occur in kidney failure are yet to be fully delineated. Angiotensin-converting enzyme (ACE) 2 is a newly described enzyme that is expressed in the heart and plays an important role in cardiac function. This study assessed whether ACE2 plays a role in the cardiac remodelling that occurs in experimental acute kidney injury (AKI). Sprague-Dawley rats had sham (control) or subtotal nephrectomy surgery (STNx). Control rats received vehicle (n = 10), and STNx rats received the ACE inhibitor (ACEi) ramipril, 1 mg kg(-1) day(-1) (n = 15) or vehicle (n = 13) orally for 10 days after surgery. Rats with AKI had polyuria (P < 0.001), proteinuria (P < 0.001) and hypertension (P < 0.001). Cardiac structural changes were present and characterized by LVH (P < 0.001), fibrosis (P < 0.001) and increased cardiac brain natriuretic peptide (BNP) mRNA (P < 0.01). These changes occurred in association with a significant increase in cardiac ACE2 gene expression (P < 0.01) and ACE2 activity (P < 0.05). Ramipril decreased blood pressure (P < 0.001), LVH (P < 0.001), fibrosis (P < 0.01) and BNP mRNA (P < 0.01). These changes occurred in association with inhibition of cardiac ACE (P < 0.05) and a reduction in cardiac ACE2 activity (P < 0.01). These data suggest that AKI, even at 10 days, promotes cardiac injury that is characterized by hypertrophy, fibrosis and increased cardiac ACE2. Angiotensin-converting enzyme 2, by promoting the production of the antifibrotic peptide angiotensin(1-7), may have a cardioprotective role in AKI, particularly since amelioration of adverse cardiac effects with ACE inhibition was associated with normalization of cardiac ACE2 activity.
Burchill
L
L
Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria 3081, Australia.
Velkoska
E
E
Dean
R G
RG
Lew
R A
RA
Smith
A I
AI
Levidiotis
V
V
Burrell
L M
LM
D058186:Acute Kidney Injury / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D000085962:Angiotensin-Converting Enzyme 2; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001345:Autoradiography; D001794:Blood Pressure / Q000502:physiology; D001835:Body Weight / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D004326:Drinking / Q000502:physiology; D005456:Fluorescent Dyes; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D006334:Heart Function Tests; D006339:Heart Rate / Q000502:physiology; D007677:Kidney Function Tests; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology*; D009392:Nephrectomy; D007703:Peptidyl-Dipeptidase A / Q000096:biosynthesis*; D011507:Proteinuria / Q000209:etiology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014563:Urodynamics / Q000502:physiology; D020257:Ventricular Remodeling / Q000502:physiology*
D000806:Angiotensin-Converting Enzyme Inhibitors; D005456:Fluorescent Dyes; D012333:RNA, Messenger; D003094:Collagen; D007703:Peptidyl-Dipeptidase A; C000705329:Ace2 protein, rat; D000085962:Angiotensin-Converting Enzyme 2