IntroductionEssential hypertension is characterized by increased neurohumoral activation. Central Angiotensin II (AngII) increases sympathetic outflow. Our previous studies showed dysfunctional central ACE2/Ang1‐7/Mas receptor axis and increased ACE in heart failure animals with increased sympathetic activation. Mice overexpressing the human isoform of ACE2 (synhACE2) in the brain exhibit reduced sympathetic nerve activity (SNA) and a reduction in central oxidant stress. However, the mechanism by which ACE2 overexpression alters neurohumoral outflow is unknown. Our preliminary experiments showed evidence of increased central Nrf2, a redox sensitive transcription factor, in synhACE2 mice with heart failure. Nrf2 promotes antioxidant enzyme expression, but the role of this pathway in the central regulation of sympathetic outflow in response to central Ang II has not been explored.HypothesisWe hypothesized that upregulation of central ACE2 inhibits the pressor response to AngII by a Nrf2–related, antioxidant effect.MethodssynhACE2+ mice and their synhACE2‐ littermates/wild type controls (n=3–7/group) were used to evaluate blood pressure, metabolic responses, Nrf2, antioxidant enzyme expression and oxidative stress in the brain during and following 2 weeks of intracerebroventricular (icv) AngII (100 ng/kg/min) infusion. In vitro experiments were carried out using Neuro 2A cells to assess Nrf2 translocation to the nucleus in response to AngII (100 nM/24 hrs) stimulation.Resultsicv AngII induced a significant increase in mean arterial blood pressure and polydipsia (Fig.1), as well as 24‐hour norepinephrine (NE) excretion. Brain selective overexpression of synhACE2 attenuated the blood pressure (95.2 ± 4.3 mmHg vs 125.4 ± 13.1 mmHg, p<0.05), polydipsia (11.3 ± 2.5mL/day vs 27.0 ± 2.0mL/day, p<0.05) and NE in response to central Ang II (Fig.1). The Mas receptor agonist Ang1‐7 and blockade (A779) had no effects on blood pressure or drinking responses following central Ang II infusion (Fig.1). In Neuro 2A cells, nuclear Nrf2 increased in response to AngII treatment.ConclusionsThese data indicate that the hypertensive effects of icv AngII are attenuated by brain selective overexpression of synACE2—most likely mediated by the effects of ACE2 on Ang II‐AT1R signaling. These data reinforce our previous finding that brain‐selective overexpression of ACE2 attenuates sympathetic nerve activity in CHF. The cell data show that AngII is capable of translocating Nrf2 to the nucleus, which is counteracted by common antioxidants, reflecting acute Nrf2 response to oxidative stress changes.Support or Funding InformationSupported by NIH grant P01 HL62222 and a UNMC pre‐doctoral fellowshipThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.