Stimulation of the Prorenin Receptor in the Paraventricular Nucleus Increases Sympathetic Outflow in Anesthetized Rat

Previous studies indicate that activation of brain prorenin receptors (PRR) contributes to hypertension. However, the detailed mechanism underlying the role of brain PRR on blood pressure control is not well understood. Here we investigated the hypothesis that stimulation of PRR in the hypothalamic paraventricular nucleus (PVN) results in an increase in sympathetic nerve activity (SNA) and therefore contributes to neurogenic hypertension. In anaesthetized adult Sprague Dawley (SD) rats, bilateral PVN microinjection of prorenin (2 pmol/side) increased splanchnic SNA (SSNA) (71±15%, n=7) and renal SNA (RSNA) (21±10%, n=7). Pre‐injection of the prorenin handle region peptide, a PRR binding blocker (PRRB), into the PVN, significantly attenuated the elevation in the SSNA (32±5%; p<0.05 vs. vehicle control; n=6) but did not block the increase in RSNA (3±11%; p=0.24 vs vehicle control; n=7) evoked by prorenin injection. We further investigated the effect of PRR activation on downstream gene expression using cultured brain neurons from the hypothalamus containing the PVN of newborn SD rats. Incubation of cultured neurons with prorenin (100 nM) for 6 hours resulted in a time‐dependent increase in the mRNA levels of iNOS (210‐fold) and Fosl1 (11‐fold), a marker for neuronal activation. In addition, increasing the availability of PRR ligand, renin, dramatically increased ROS production. All these increases were not attenuated by the AT1 receptor antagonist, losartan, indicating these effects are not mediated by PRR‐mediated AngII generation. Our results suggest that PRR induced increase in sympathetic outflow maybe through activation of the iNOS and ROS signal pathway. (AHA 11SDG7420029 and AHA2640130)