Synergism between Angiotensin AT1 and AT2 Receptors function: Role of Angiotensin‐(1‐7) via AT1R in Modulating AT2R Agonist Response on Nitric Oxide in Kidney Cells

Abstract

Angiotensin‐(1‐7) is evidently considered as an endogenous agonist for Mas receptor. Our recent studies show that MasR and AT2R physically interact and in response to their respective agonists Ang‐(1‐7) and C21 produce interdependent functional response in terms of nitric oxide (NO) generation and natriuresis. Moreover, recent studies suggest that Ang‐(1‐7) is cardio‐protective via AT1R stimulation. Considering the complex nature of Ang‐(1‐7) function, we tested as to how Ang‐(1‐7) affects AT2R function utilizing human kidney proximal tubule epithelial cells (HK‐2 cells). The agonists of MasR [(Ang‐(1‐7), AVE0991] or AT2R (C21), alone significantly stimulated NO formation at 10−6–10−5M (50–300%), but not at lower concentrations (10−12‐10−7M). Contrarily, Ang‐II alone reduced NO formation. In the interaction studies, the non‐responsive concentrations of Ang‐(1‐7) (10−12‐10−7M) synergized NO formation of C21 (10−12‐10−9M) or ang‐II (10−12‐10−9M) in HK‐2 cells (p<0.05 vs. either agonist alone). The synergy is observed only when the Ang‐(1‐7) was added to the HK‐2 cells 10 min prior to the C21/ang‐II, not when the agonists were added simultaneously. The synergy between Ang‐(1‐7) and C21/ang‐II was sensitive to AT2R antagonist (PD123319, 10−5M) and AT1R antagonist (candesartan, 10−5M), but not MasR antagonist (A779, 10−5M). Interestingly, pre‐stimulation with synthetic non‐peptide MasR selective agonist AVE0991 at any concentrations (10−10‐10−7M) did not show synergism with the AT2R agonist C21. Collectively, results show Ang‐(1‐7) at lower concentrations via AT1R, not MasR, synergies the AT2R function of NO formation and this phenomenon may have a physiological significance.Support or Funding InformationNIH R01 DK61578 and R01 DK117495