Angiotensinogen gene-activating elements regulate blood pressure in the brain

Although the angiotensinogen gene is a possible candidate as a determinant of hypertension, the molecular mechanisms of tissue angiotensinogen gene re gulation have yet to be clarified. We identified essential transcription re gulators of angiotensinogen production in the central nervous system using synthetic double-stranded oligodeoxynucleotides (ODNs) as "decoy" cis eleme nts to block the binding of nuclear factors to promoter regions of the targ eted gene. Using a gel mobility shift assay, angiotensinogen gene-activatin g element (AGE) 2 binding protein was detected in the brain nuclear extract s of both spontaneously hypertensive rats (SHRs) and normotensive Wistar Ky oto rats (WKYs). Importantly, the binding activity of AGE 2 and angiotensin ogen 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 misma tched, 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 effec ts is confirmed by the fact that no changes in circulating levels of angiot ensinogen or angiotensin II concentrations were observed. Notably, AGE 2 de coy 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 r at model.