Effects of Angiotensin 1-7 and Mas Receptor Agonist on Renal System in a Rat Model of Heart Failure

Abstract

Congestive heart failure (CHF) is often associated with impaired kidney function. Over- activation of the renin-angiotensin-aldosterone system (RAAS) contributes to avid salt/water retention and cardiac hypertrophy in CHF. While the deleterious effects of angiotensin II (Ang II) in CHF are well established, the biological actions of angiotensin 1-7 (Ang 1-7) are not fully characterized. In this study, we assessed the acute effects of Ang 1-7 (0.3, 3, 30 and 300 ng/kg/min, IV) on urinary flow (UF), urinary Na⁺ excretion (UNaV), glomerular filtration rate (GFR) and renal plasma flow )RPF) in rats with CHF induced by the placement of aortocaval fistula. Additionally, the chronic effects of Ang 1-7 (24 µg/kg/h, via intra-peritoneally implanted osmotic minipumps) on kidney function, cardiac hypertrophy and neurohormonal status were studied. Acute infusion of either Ang 1-7 or its agonist, AVE 0991, into sham controls, but not CHF rats, increased UF, UNaV, GFR, RPF and urinary cGMP. In the chronic protocols, untreated CHF rats displayed lower cumulative UF and UNaV than their sham controls. Chronic administration of Ang 1-7 and AVE 0991 exerted significant diuretic, natriuretic and kaliuretic effects in CHF rats, but not in sham controls. Serum creatinine and aldosterone levels were significantly higher in vehicle-treated CHF rats as compared with controls. Treatment with Ang 1-7 and AVE 0991 reduced these parameters to comparable levels observed in sham controls. Notably, chronic administration of Ang 1-7 to CHF rats reduced cardiac hypertrophy. In conclusion, Ang 1-7 exerts beneficial renal and cardiac effects in rats with CHF. Thus, we postulate that ACE2/Ang 1-7 axis represents a compensatory response to over-activity of ACE/AngII/AT1R system characterizing CHF and suggest that Ang 1-7 may be a potential therapeutic agent in this disease state.

Keywords: ACE2; MasR; angiotensin 1-7; heart failure; kidney.

Figure 1

Acute changes from baseline in urinary flow (UF), urinary sodium excretion (UNaV) and fractional sodium excretion (FENa) following acute infusion of increasing doses of Ang 1-7 (A,C,E) and AVE 0991 (B,D,F) in control or CHF rats. One-way ANOVA followed by Tukey test was applied within group comparisons in the acute studies. * p < 0.05, ** p < 0.01, *** p < 0.001 vs. baseline values.

Figure 2

Acute changes in glomerular filtration rate (GFR), renal plasma flow (RPF) and mean arterial blood pressure (MAP) following acute infusion of increasing doses of Ang 1-7 (A,C,E) and AVE 0991 (B,D,F) in control or CHF rats. One-way ANOVA followed by Tukey test was applied within group comparisons in the acute studies. * p < 0.05, ** p < 0.01, *** p < 0.001 vs. baseline values.

Figure 3

Changes in urinary excretion of cGMP normalized to GFR in CHF and control rats following acute treatment with incremental doses of Ang 1-7 (A) or AVE 0991 (B). One-way ANOVA followed by Tukey test was applied within group comparisons in the acute studies. * p < 0.05, ** p < 0.01, *** p < 0.001 CHF vs. sham controls, or treated CHF and sham vs. corresponding untreated subgroups.

Figure 4

Effects of chronic treatment with Ang 1-7 and its mimetic (AVE 0991) on cumulative urinary flow (UF), Na⁺ excretion (U_NaV) and K+ excretion (U_KV) in control rats (A,C,E) and CHF animals (B,D,F). Cumulative urine volume (A,B), sodium excretion (C,D) and potassium excretion (E,F) in control rats and in CHF rats chronically treated with Ang 1-7 or AVE 0079 at a dose of 24 µg/kg/h i.p. or vehicle via osmotic minipumps for 28 days. Baseline values refer to 5-day collection periods (days 1–5) prior to initiation of the various treatment. * p < 0.05, ** p < 0.01, *** p < 0.001 compared with untreated CHF. Two-way ANOVA followed with Bonferroni post-tests was used to compare between treated and untreated animal groups.

Figure 5

Effects of chronic treatment with Ang 1-7 and its mimetic (AVE 0991) on absolute kidney weight (KW) (A), normalized kidney weight to body weight (KW/BW%) (B), serum creatinine (sCr) (C) and daily urinary cGMP excretion (UcGMP*V) (D) after 2 and 4 weeks of treatment of control rats and CHF animals. One-way ANOVA followed by Tukey test was applied within group comparisons in the acute studies. * p < 0.05, ** p < 0.01, *** p < 0.001 between CHF and their sham controls or treated and untreated CHF animals or sham controls.

Figure 6

Effects of chronic treatment with Ang 1-7 and its mimetic (AV E0991) on absolute heart weight (HW) (A), normalized heart weight to body weight (HW/BW) (B) after 4 weeks of treatment and plasma BNP levels (C), after 2 and 4 weeks of treatment of control rats and CHF animals. One-way ANOVA followed by Tukey test was applied within group comparisons in the acute studies. * p < 0.05, ** p < 0.01, *** p < 0.001 between CHF and their sham controls or treated and untreated CHF animals or sham controls.

Figure 7

Effects of chronic treatment with Ang 1-7 and its mimetic (AVE 0991) on plasma aldosterone (A) and angiotensin II (B) levels after 2 and 4 weeks of treatment of control rats and CHF animals. One-way ANOVA followed by Tukey test was applied within group comparisons in the acute studies. * p < 0.05, ** p < 0.01, *** p < 0.001 between CHF and their sham controls or treated and untreated CHF animals or sham controls.