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Long‐term interactions between the ACE/Ang II/AT1a receptor axis and the ACE2/Ang(1–7)/Mas receptor axis in wild‐type C57BL/6J and AT1a receptor‐knockout mice

The present study tested the hypothesis that long‐term hypertensive and renal effects of angiotensin II (Ang II) are antagonized by the activation of the ACE2/Ang (1–7)/Mas receptor axis in C57BL/6J (WT) and AT1a‐KO mice. An equi‐dose of Ang II, Ang (1–7), or in combination, was infused in WT or AT1a‐KO mice continuously for 12 weeks (800 ng/kg/min, i.p.). In WT mice, Ang II increased systolic blood pressure (SBP) in a time‐dependent manner (Basal: 119 ± 6 vs. Week 12: 150 ± 7 mmHg, p<0.01). Ang (1–7) alone had no effect on SBP (Week 12: 119 ± 3 mmHg, n.s.) or on Ang II‐induce hypertension (Week 12: 146 ± 8 mmHg, n.s. vs. Ang II alone). In AT1a‐KO mice, basal SBP was significantly lower than in WT mice, which was not altered by Ang II. However, Ang (1–7) significantly decreased SBP in AT1a‐KO mice (Basal: 107 ± 4 vs. Week 12: 90 ± 2 mmHg, p<0.01). In the kidney, both Ang II and Ang (1–7) slightly increased 24 hour urine and urinary sodium excretion, and this effect was not altered by combination‐infusion in WT mice. Furthermore, Ang II significantly increased the levels of phosphorylated sodium and hydrogen exchanger‐3 in the renal cortex of WT mice (p<0.01), which was not blocked by co‐administration with Ang (1–7). We therefore conclude that the activation of the ACE2/Ang (1–7)/Mas receptor axis is unlikely to fully counter‐balance the long‐term blood pressure and renal effects induced by the ACE/Ang II/AT1 receptor axis.