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Angiotensinogen gene-activating elements regulate blood pressure in the brain
T Nishii1, A Moriguchi, R Morishita
1Department of Geriatric Medicine, Osaka University Medical School, Tsukuba, Japan.
Circulation Research
|August 7, 1999
Summary
Abnormal expression of a brain protein, AGE 2, significantly increases blood pressure in hypertensive rats. Targeting this protein with decoy oligodeoxynucleotides (ODNs) lowered blood pressure by reducing brain angiotensinogen.
Area of Science:
- Neuroscience
- Molecular Biology
- Cardiovascular Research
Background:
- The angiotensinogen gene is implicated in hypertension, but its central regulatory mechanisms remain unclear.
- Understanding tissue-specific gene regulation is crucial for developing targeted therapies.
Purpose of the Study:
- To identify key transcription regulators of angiotensinogen production in the central nervous system.
- To investigate the role of these regulators in a genetic model of hypertension.
Main Methods:
- Utilized synthetic double-stranded oligodeoxynucleotides (ODNs) as decoy cis elements to block nuclear factor binding.
- Employed gel mobility shift assays to detect protein-DNA interactions.
- Administered decoy ODNs into the lateral cerebroventricle of spontaneously hypertensive rats (SHRs) and Wistar Kyoto rats (WKYs).
Main Results:
- A specific binding protein, AGE 2, was detected in rat brain nuclear extracts.
- AGE 2 binding activity and angiotensinogen mRNA levels were significantly higher in SHRs compared to WKYs.
- Transfection of AGE 2 decoy ODNs into SHRs reduced blood pressure, brain angiotensinogen, and angiotensin II levels without affecting circulating levels.
Conclusions:
- Abnormal expression of AGE 2 binding protein in the central nervous system is crucial for high blood pressure in a genetic rat model.
- Targeting AGE 2 offers a potential therapeutic strategy for hypertension via central mechanisms.