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: Wencheng Li, Hua Peng, Theresa Cao, Ryosuke Sato, Sarah J McDaniels, Hiroyuki Kobori, L Gabriel Navar, Yumei Feng
• Journal: Hypertension (Dallas, Tex. : 1979) (Hypertension) Vol. 59 Issue 6 Pg. 1188-94 (Jun 2012) ISSN: 1524-4563 [Electronic] United States
• PMID: 22526255 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Receptor, Angiotensin, Type 1
• Receptors, Cell Surface
• Vasopressins
• Angiotensinogen
• Angiotensin II
• Renin
• Prorenin Receptor

Topics

• Angiotensin II (blood, metabolism)
• Angiotensinogen (deficiency, genetics)
• Animals
• Baroreflex (genetics, physiology)
• Blood Pressure (genetics, physiology)
• Blotting, Western
• Brain (metabolism)
• Cell Line, Tumor
• Humans
• Hypertension (genetics, metabolism, physiopathology)
• Immunohistochemistry
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Neurons (metabolism)
• RNA Interference
• Receptor, Angiotensin, Type 1 (genetics, metabolism)
• Receptors, Cell Surface (genetics, metabolism)
• Renin (deficiency, genetics)
• Reverse Transcriptase Polymerase Chain Reaction
• Vasopressins (blood, genetics, metabolism)
• Prorenin Receptor