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(Circulation Research. 1999;85:257-263.)
© 1999 American Heart Association, Inc.

Original Contribution

Angiotensinogen Gene–Activating Elements Regulate Blood Pressure in the Brain

Tadahiko Nishii, Atsushi Moriguchi, Ryuichi Morishita, Kazuo Yamada, Shigefumi Nakamura, Naruya Tomita, Yasufumi Kaneda, Akiyoshi Fukamizu, Hiroshi Mikami, Jitsuo Higaki, Toshio Ogihara

From the Departments of Geriatric Medicine (T.N., A.M., R.M., K.Y., S.N., N.T., H.M., J.H., T.O.) and Gene Therapy Science (R.M., Y.K.), Osaka University Medical School, and Department of Applied Biochemistry (A.F.), University of Tsukuba, Tsukuba, Japan.

Correspondence to Toshio Ogihara, MD, Department of Geriatric Medicine, Osaka University Medical School, 2-2 Yamada-oka, Suita 565-0821, Japan. E-mail moriguch{at}geriat.med.osaka-u.ac.jp

Abstract—Although the angiotensinogen gene is a possible candidate as a determinant of hypertension, the molecular mechanisms of tissue angiotensinogen gene regulation have yet to be clarified. We identified essential transcription regulators of angiotensinogen production in the central nervous system using synthetic double-stranded oligodeoxynucleotides (ODNs) as "decoy" cis elements to block the binding of nuclear factors to promoter regions of the targeted gene. Using a gel mobility shift assay, angiotensinogen gene–activating element (AGE) 2 binding protein was detected in the brain nuclear extracts of both spontaneously hypertensive rats (SHRs) and normotensive Wistar Kyoto rats (WKYs). Importantly, the binding activity of AGE 2 and angiotensinogen mRNA level were significantly higher in the brain of SHRs than in that of WKYs. Using the decoy approach, we demonstrated a significant decrease in the blood pressure of SHRs by transfection of AGE 2 decoy, but not mismatched, ODNs into the lateral cerebroventricle, accompanied by a significant decrease in brain angiotensinogen concentration and mRNA, and angiotensin II level. That these effects, demonstrated herein, are due to central effects is confirmed by the fact that no changes in circulating levels of angiotensinogen or angiotensin II concentrations were observed. Notably, AGE 2 decoy ODNs did not decrease the blood pressure of WKYs. We conclude that the abnormal expression of AGE 2 binding protein in the central nervous system plays a crucial role in high blood pressure of a genetically hypertensive rat model.

Key Words: transcriptional cis element • central nervous system • HVJ-liposome method • renin-angiotensin system • decoy oligodeoxynucleotide

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