title: Brain-targeted (pro)renin receptor knockdown attenuates angiotensin II-dependent hypertension.
abstract: 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.
authors.affiliation: Department of Physiology, Tulane Hypertension and Renal Center of Excellence, Tulane University School of Medicine, New Orleans, LA 70112, USA.
authors.forename: Wencheng
authors.initials: W
authors.lastname: Li
authors.forename: Hua
authors.initials: H
authors.lastname: Peng
authors.forename: Theresa
authors.initials: T
authors.lastname: Cao
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Sato
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: McDaniels
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kobori
authors.forename: L Gabriel
authors.initials: LG
authors.lastname: Navar
authors.forename: Yumei
authors.initials: Y
authors.lastname: Feng
mesh_terms: D000804:Angiotensin II / Q000097:blood / Q000378:metabolism*; D000808:Angiotensinogen / Q000172:deficiency / Q000235:genetics; D000818:Animals; D017704:Baroreflex / Q000235:genetics / Q000502:physiology; D001794:Blood Pressure / Q000235:genetics / Q000502:physiology; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism*; D045744:Cell Line, Tumor; D006801:Humans; D006973:Hypertension / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism; D034622:RNA Interference; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D012083:Renin / Q000172:deficiency / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014667:Vasopressins / Q000097:blood / Q000235:genetics / Q000378:metabolism; D000093342:Prorenin Receptor
chemical_list: D044140:Receptor, Angiotensin, Type 1; D011956:Receptors, Cell Surface; D014667:Vasopressins; D000808:Angiotensinogen; D000804:Angiotensin II; D012083:Renin; D000093342:Prorenin Receptor