We investigated the mechanism by which ACE2 (angiotensin-converting enzyme 2) overexpression alters neurohumoral outflow and central oxidative stress. Nrf2 (nuclear factor [erythroid-derived 2]-like 2) is a master antioxidant transcription factor that regulates cytoprotective and antioxidant genes. We hypothesized that upregulation of central ACE2 inhibits the pressor response to Ang II (angiotensin II) by reducing reactive oxygen species through a Nrf2/antioxidant enzyme-mediated mechanism in the rostral ventrolateral medulla. Synapsin human Angiotensin Converting Enzyme 2 positive (SynhACE2(+/+)) mice and their littermate controls synhACE2(-/-)were used to evaluate the consequence of intracerebroventricular infusion of Ang II. In control mice, Ang II infusion evoked a significant increase in blood pressure and norepinephrine excretion, along with polydipsia and polyuria. The pressor effect of central Ang II was completely blocked in synhACE2(+/+)mice. Polydipsia, norepinephrine excretion, and markers of oxidative stress in response to central Ang II were also reduced in synhACE2(+/+)mice. The MasR (Mas receptor) agonist Ang 1-7 and blocker A779 had no effects on blood pressure. synhACE2(+/+)mice showed enhanced expression of Nrf2 in the rostral ventrolateral medulla which was blunted following Ang II infusion. Ang II evoked nuclear translocation of Nrf2 in cultured Neuro 2A (N2A) cells. In synhACE2(-/-)mice, the central Ang II pressor response was attenuated by simultaneous intracerebroventricular infusion of the Nrf2 activator sulforaphane; blood pressure was enhanced by knockdown of Nrf2 in the rostral ventrolateral medulla in Nrf2 floxed (Nrf2(f/f)) mice. These data suggest that the hypertensive effects of intracerebroventricular Ang II are attenuated by selective overexpression of brain synhACE2 and may be mediated by Nrf2-upregulated antioxidant enzymes in the rostral ventrolateral medulla.