Angiotensin-(1-7) infusion is associated with increased blood pressure and adverse cardiac remodelling in rats with subtotal nephrectomy

Abstract

ACE (angiotensin-converting enzyme) 2 is expressed in the heart and kidney and metabolizes Ang (angiotensin) II to Ang-(1-7) a peptide that acts via the Ang-(1-7) or mas receptor. The aim of the present study was to assess the effect of Ang-(1-7) on blood pressure and cardiac remodelling in a rat model of renal mass ablation. Male SD (Sprague-Dawley) rats underwent STNx (subtotal nephrectomy) and were treated for 10 days with vehicle, the ACE inhibitor ramipril (oral 1 mg·kg(-1) of body weight·day(-1)) or Ang-(1-7) (subcutaneous 24 μg·kg(-1) of body weight·h(-1)) (all n = 15 per group). A control group (n = 10) of sham-operated rats were also studied. STNx rats were hypertensive (P<0.01) with renal impairment (P<0.001), cardiac hypertrophy (P<0.001) and fibrosis (P<0.05), and increased cardiac ACE (P<0.001) and ACE2 activity (P<0.05). Ramipril reduced blood pressure (P<0.01), improved cardiac hypertrophy (P<0.001) and inhibited cardiac ACE (P<0.001). By contrast, Ang-(1-7) infusion in STNx was associated with further increases in blood pressure (P<0.05), cardiac hypertrophy (P<0.05) and fibrosis (P<0.01). Ang-(1-7) infusion also increased cardiac ACE activity (P<0.001) and reduced cardiac ACE2 activity (P<0.05) compared with STNx-vehicle rats. Our results add to the increasing evidence that Ang-(1-7) may have deleterious cardiovascular effects in kidney failure and highlight the need for further in vivo studies of the ACE2/Ang-(1-7)/mas receptor axis in kidney disease.

Figure 1. Systolic blood pressure (A), ventricular contractility (B), time constant of isovolumic relaxation (C) and LVEDP (D) in control and STNx [vehicle, ramipril and Ang-(1–7)] rats

Values are means±S.E.M. (n = 10 for the control group and n = 15 for the STNx groups). **P<0.01 compared with control; ^#P<0.05 and ^##P<0.01 compared with vehicle-treated STNx.

Figure 2. Left ventricular hypertrophy (A), interstitial collagen (B), ACE binding (C) and ACE2 activity (D) in control and STNx [vehicle, ramipril and Ang-(1–7)] rats

Values are means±S.E.M. (n = 10 for the control group and n = 15 for the STNx groups) *P<0.05 and ***P<0.001 compared with control; ^#P<0.05, ^##P<0.01 and ^###P<0.001 compared with vehicle-treated STNx.

Figure 3. Representative photomicrographs of left ventricular total collagen content (red staining; left-hand panel) and representative macroscopic autoradiographs demonstrating ACE binding in the LV (right-hand panel)

The red colour denotes the highest density of radiolabelling, whereas the blue colour represents background labelling.

Figure 4. Schematic representation of possible mechanisms responsible for the adverse effects of Ang-(1–7) administration in STNx

Exogenous administration of Ang-(1–7) results in increased ACE activity , leading to increased levels of AngII, which bind to AT₁R and activate the pressor arm of the RAS system. Furthermore, excess Ang-(1–7) can also be broken down to Ang-(3–7), a potent agonist of the AT₄R , which has been shown to contribute to cardiovascular disease via the activation of the NF-κB (nuclear factor κB) pathway. Activation of the AT₄R by AngIV, a metabolite of AngII may play a role . Finally, reduced renal excretion of angiotensin metabolites may also be contributing to the effects observed in the present study.