The prevalence of kidney disease is increasing worldwide with cardiovascular disease being the major cause of morbidity and mortality. Subtotal nephrectomy (STNx) in rats leads to impaired kidney function, activation of the traditional renin angiotensin system (RAS) pathway and adverse cardiac remodelling. Angiotensin converting enzyme (ACE) 2 is an important modulator of the RAS through its role to degrade angiotensin II, and tissue ACE2 depletion may contribute to disease progression. We investigated the cardiac effects of the ACE2 activator diminazene aceturate (DIZE) in STNx rats compared to RAS blockade using the ACE inhibitor ramipril.Design and Method:
Female Sprague Dawley rats underwent STNx and received 4 weeks treatment with vehicle, ramipril (oral 1 mg/kg) or DIZE (s.c 15 mg/kg/day). Control rats received vehicle (all groups, n = 10/gp). Blood pressure and cardiac function were measured by cardiac catheterisation.Results:
STNx rats were hypertensive (P < 0.01) with diastolic dysfunction (P < 0.05), left ventricular hypertrophy (LVH; P < 0.001), interstitial fibrosis (P < 0.05), and elevated cardiac BNP mRNA (P < 0.01). STNx rats had elevated cardiac ACE activity (P < 0.05 vs. Control) but no change in ACE2 activity. In STNx, ramipril and DIZE reduced blood pressure (both P < 0.001), and improved diastolic function, LVH and interstitial fibrosis (all P < 0.05 vs. STNx-vehicle), but only ramipril reduced BNP mRNA (P < 0.05). The cardiac benefits of DIZE were associated with increased cardiac ACE2 activity and restoration of the ACE/ACE2 balance.Conclusions:
DIZE shifted the cardiac ACE and ACE2 activity balance to a cardioprotective profile in STNx rats, with beneficial effects on LVH and fibrosis that were similar to those of ramipril. Studies are now needed to investigate if combining DIZE with standard RAS blockade has additive effects to improve the cardiac consequences of kidney disease.