A local renin-angiotensin system (RAS) is evident within the renal proximal tubules and overexpression of the precursor angiotensinogen targeted to the tubules increases blood pressure and promotes renal injury. Tubular angiotensinogen is enhanced by the Ang II-AT1 receptor axis, oxidative stress and pro-inflammatory cytokines (IL-6, TGFβ), as well as hyperglycemic conditions. Stimulation of angiotensinogen by the Ang II-AT1 receptor pathway constitutes a positive-feedback loop that may promote a sustained increase in blood pressure and renal damage. Mediators that promote angiotensinogen also attenuate the expression of the ACE2-Ang-(1-7) axis. Downregulation of the Ang-(1-7) axis and its associated signaling pathways may contribute to greater expression of angiotensinogen within the kidney. To examine this potential pathway, we assessed the chronic effects of the Ang-(1-7) agonist AVE0991 on angiotensinogen release in human HK-2 proximal epithelial cells maintained under mild hyperglycemic conditions. HK-2 cells were placed in serum-free media and then treated with varying doses of the AVE0991 agonist (0.1 nM to 1 uM) for up to 48 hours. Human angiotensinogen was quantified in the cell media by ELISA with a sensitivity of 30 picogram (pg). Basal release of angiotensinogen at 48 hrs was 1.47 ± 0.28 ng/ml (n=4). Addition of 0.1 nM AVE0991 attenuated angiotensinogen release by 23 ± 4%, p<0.05 with a maximal inhibitory effect of 48 ± 9%, p<0.05 [n=3]. AVE0991 at the maximal dose had no detrimental effect on cell viability. The NOS inhibitor LNAME (100 uM) failed to block the inhibitory effect of AVE0991 and LNAME alone did not influence release. Addition of the AT2R agonist C21 (1 uM) had no effect on angiotensinogen release. The Ang-(1-7) receptor antagonist [D-Pro 7 ]-Ang-(1-7) blocked the inhibitory effects of AVE0991; however, [D-Ala 7 -Ang-(1-7)(A779), losartan, PD123319 or the kinin B2 receptor HOE140 had no effect. We conclude that the Ang-(1-7) axis may exert negative feedback on the tubular angiotensin system and that the renoprotective effects of AVE0991 may reflect attenuation of angiotensinogen release. Furthermore, the inhibitory actions of AVE0091 on the tubular release of angiotensinogen appear to be independent of the NOS-NO pathway.