Activation of the (pro)renin receptor in the paraventricular nucleus increases sympathetic outflow in anesthetized rats. Am J Physiol Heart Circ Physiol 309: H880 -H887, 2015. First published June 26, 2015 doi:10.1152/ajpheart.00095.2015.-Previous studies have indicated that hyperactivity of brain prorenin receptors (PRR) is implicated in neurogenic hypertension. However, the role of brain PRR in regulating arterial blood pressure (ABP) is not well understood. Here, we test the hypothesis that PRR activation in the hypothalamic paraventricular nucleus (PVN) contributes to increased sympathetic nerve activity (SNA). In anaesthetized adult Sprague-Dawley (SD) rats, bilateral PVN microinjection of human prorenin (2 pmol/side) significantly increased splanchnic SNA (SSNA; 71 Ϯ 15%, n ϭ 7). Preinjection of either prorenin handle region peptide, the PRR binding blocker (PRRB), or tiron (2 nmol/side), the scavenger of reactive oxygen species (ROS), significantly attenuated the increase in SSNA (PRRB: 32 Ϯ 5% vs. control, n ϭ 6; tiron: 8 Ϯ 10% vs. control, n ϭ 5; P Ͻ 0.05) evoked by prorenin injection. We further investigated the effects of PRR activation on ROS production as well as downstream gene expression using cultured hypothalamus neurons from newborn SD rats. Incubation of brain neurons with human prorenin (100 nM) dramatically enhanced ROS production and induced a time-dependent increase in mRNA levels of inducible nitric oxide synthase (iNOS), NAPDH oxidase 2 subunit cybb, and FOS-like antigen 1 (fosl1), a marker for neuronal activation and a component of transcription factor activator protein-1 (AP-1). The maximum mRNA increase in these genes occurred 6 h following incubation (iNOS: 201-fold; cybb: 2 -fold; Ffosl1: 11-fold). The increases in iNOS and cybb mRNA were not attenuated by the AT 1 receptor antagonist losartan but abolished by the AP-1 blocker curcumin. Our results suggest that PVN PRR activation induces sympathoexcitation possibly through stimulation of an ANG II-independent, ROS-AP-1-iNOS signaling pathway. paraventricular nucleus; (pro)renin receptor; reactive oxygen species; sympathetic nerve activity NEW & NOTEWORTHY To our best knowledge, this study is the first to investigate PVN PRR-mediated ANG II-independent signaling transduction on the control of sympathetic outflow and blood pressure. Our results suggest that PVN PRR-induced sympathoexcitation is possibly mediated by ROS-AP-1-iNOS signal transduction pathways.ACCUMULATING EVIDENCE INDICATES that alteration of central (pro)renin receptor (PRR) is involved in the development of cardiovascular diseases including neurogenic hypertension (32,46). The importance of the brain PRR in cardiovascular control is further strengthened by the observation that increased PRR expression in brain cardiovascular control areas altered body fluid homeostasis (38) and genetic knockdown of the PRR induced long-term depressor effects in hypertensive animals (21,22,38). However, the detailed mechanism underlying the role of brain PRR on blood pressure regulati...