Brain-Targeted (Pro)renin Receptor Knockdown Attenuates Angiotensin II-Dependent Hypertension

The (pro) renin receptor is a newly discovered member of the brain renin-angiotensin system. To investigate the role of brain (pro) renin receptor in hypertension, adeno-associated virus-mediated (pro) renin receptor short hairpin RNA was used to knockdown (pro) renin receptor expression in the brain of nontransgenic normotensive and human renin-angiotensinogen double-transgenic hypertensive mice. Blood pressure was monitored using implanted telemetric probes in conscious animals. Real-time PCR and immunostaining were performed to determine (pro) renin receptor, angiotensin II type 1 receptor, and vasopressin mRNA levels. Plasma vasopressin levels were determined by ELISA. Double-transgenic mice exhibited higher blood pressure, elevated cardiac and vascular sympathetic tone, and impaired spontaneous baroreflex sensitivity. Intracerebroventricular delivery of (pro) renin receptor short-hairpin RNA significantly reduced blood pressure, cardiac and vasomotor sympathetic tone, and improved baroreflex sensitivity compared with the control virus treatment in double-transgenic mice. (Pro) renin receptor knockdown significantly reduced angiotensin II type 1 receptor and vasopressin levels in double-transgenic mice. These data indicate that (pro) renin receptor knockdown in the brain attenuates angiotensin II-dependent hypertension and is associated with a decrease in sympathetic tone and an improvement of the baroreflex sensitivity. In addition, brain-targeted (pro) renin receptor knockdown is associated with downregulation of angiotensin II type 1 receptor and vasopressin levels. We conclude that central (pro) renin receptor contributes to the pathogenesis of hypertension in human renin-angiotensinogen transgenic mice. (Hypertension. 2012; 59: 1188-1194.). Online Data Supplement