Abstract P1100: Angiotensin-(1-7) Via Angiotensin Type-1 Receptor Synergies Angiotensin Type-2 Receptor Response of Nitrite Formation in Kidney Cells

Abstract

Angiotensin-(1-7) is evidently considered as an endogenous agonist for Mas receptor. Our recent studies show that MasR and AT 2 R 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 AT 1 R stimulation. Considering the complex nature of Ang-(1-7) function, we tested as to how Ang-(1-7) affects AT 2 R function utilizing human kidney proximal tubule epithelial cells (HK-2 cells). Ang-(1-7), C21 or AVE0991 (a MasR selective agonist), alone significantly stimulated NO formation at 1-10 μM (50-100%, n=3), but not at lower concentrations (0.1-100 nM). In the interaction studies, the non-responsive concentrations (0.1-10 nM) of Ang-(1-7) and C21 together produced a synergy in producing NO in HK-2 cells (p<0.05 vs. either ligand alone). The synergy is observed only when the Ang-(1-7) was added to the HK-2 cells 10 min prior to the C21, not if the agonists were added simultaneously. The synergy between Ang-(1-7) and C21 was sensitive to AT 2 R antagonist (PD123319, 10 μM) and AT 1 R antagonist (candesartan, 10 μM), but not MasR antagonist (A779, 10 μM). Interestingly, pre-stimulation with synthetic non-peptide MasR selective agonist AVE0991 at any concentrations (0.1-100 nM) did not show synergism with AT 2 R agonist C21. Collectively, results show Ang-(1-7) at lower concentrations via AT 1 R, not MasR, synergies the AT 2 R function and this phenomenon may have physiological significance.