The brain renin-angiotensin system plays an important role in blood pressure (BP) regulation. However, the origin of brain Ang II remains unknown due to the low brain renin activity. We previously reported that prorenin and (pro)renin receptor (PRR) is present in the brain. To test our hypothesis that prorenin mediates Ang II formation in the brain via binding to PRR, the neuron-specific PRR knockout (Nefh-PRRKO) and wild type (WT) mice (n=5/group) were implanted with telemetric probes and intracerebroventricular (ICV) cannulas. BP was recorded in conscious mice during ICV infusion (0.3µl/min) for ten minutes. ICV infusion of Ang II (100ng/µl) increased BP (ΔMAP, mmHg) in both WT (48±5) and Nefh-PRRKO (40±2)mice; and this effect was blocked by AT1 receptor blocker (Losartan) indicating that the AT1R is functionally intact in Nefh-PRRKO mice. ICV infusion of mouse prorenin (100ng/µl) induced a pressor response in WT mice (42.3±5.7), and this response was completely blocked by Losartan or Captopril suggesting that prorenin induced Ang II-dependent pressor response in WT mice. Interestingly, the pressor response to mouse prorenin was abolished in Nefh-PRRKO mice (5±1; P<0.05), indicating that prorenin mediates pressor response via binding to PRR. To determine whether PRR contributes to the development of brain RAS-dependent hypertension, Nefh-PRR and WT littermates (N=8/group) were treated with 50mg of deoxycorticosterone acetate (DOCA) subcutaneously, plus 0.9% NaCl drinking water for 21 days. The baseline BP was similar between Nefh-PRR (101 ± 2) and WT (101 ± 3) mice. BP was increased in WT mice (132 ± 6) by DOCA-salt treatment, while Nefh-PRR mice remained normotensive (108 ± 3). In summary, prorenin via PRR mediates AngII/AT1R-dependent pressor response in the brain. Neuron-specific PRR deletion attenuates the development of DOCA-salt hypertension likely due to the lack of Ang II/AT1R activation. We conclude that prorenin/PRR may be the key factors to initiate the brain RAS and play an essential role in neurogenic hypertension.