Abstract 213: Neuron-specific (Pro)renin Receptor Deletion Attenuates Neurogenic Hypertension and is Associated With Improvement of Autonomic Function

Abstract

Although (pro)renin receptor (PRR) is highly expressed in the brain, the physiological importance of brain PRR remains to be determined. We previously showed that PRR mRNA levels were up-regulated in the brain regions involved in blood pressure (BP) regulation including the subfornical organs (SFO), paraventricular nuclei (PVN), and rostral ventrolateral medulla (RVLM) in the DOCA-salt-induced hypertensive mice. To elucidate whether the increase of PRR expression contributes to the development of hypertension, we developed a neuron-specific PRR knockout mouse (Nefh-PRR) model by crossing PRR-floxed mice with mice that express Cre-recombinase with neurofilament-H (Nefh-Cre) promoter. Immunostaining showed that PRR expression was significantly reduced in cardiac regulatory brain regions including SFO (0.35± 0.15), PVN (0.34 ± 0.09), and RVLM (0.41 ± 0.1), where the Cre-recombinase was expressed, in Nefh-PRR compared to Nefh-cre mice (1 ± 0.1, 1 ± 0.19 and 1 ± 0.06). Nefh-PRR mice and Nefh-cre mice with wild type PRR gene (WT, n=8/group) were implanted with telemetric probes. BP (mmHg) and heart rate (HR, bpm) were recorded for baseline and following DOCA-salt treatment (50mg DOCA, 0.9%NaCl drinking solution, 21 days). Nefh-PRR mice exhibited normal baseline BP and HR. Following DOCA-salt treatment, BP was significantly lower in Nefh-PRR mice (108 ± 3) compared to WT mice (132 ± 6, P<0.05). The cardiac sympathetic tone (HR response to propranolol, ΔHR: -128±46vs. -180±45) and the vasomotor sympathetic tone (BP response to chlorisondamine, ΔBP: -46 ±17vs.-68± 12) were lower in Nefh-PRR than WT mice after DOCA-salt treatment. Moreover, HR response to methylatropine (ΔHR: 98±38 vs. 43±19) was greater in Nefh-PRR. In addition, DOCA-salt treatment increased plasma vasopressin (AVP) levels (33.6 ± 5.3 vs.3.0 ± 0.3pg/ml) in WT mice. PRR deletion significantly attenuated the increase in plasma AVP levels (19.0 ± 2.0pg/ml) induced by DOCA-salt. The data suggest PRR deletion prevents the development of DOCA-salt hypertension and is associated with reduction of plasma AVP levels and improvement of autonomic function. We conclude that brain PRR may be a novel therapeutic target for the treatment of hypertension.