Elevated blood pressure in transgenic mice with brain-specific expression of human angiotensinogen driven by the glial fibrillary acidic protein promoter

In addition to the circulatory renin (REN)-angiotensin system (RAS), a tiss ue RAS having an important role in cardiovascular function also exists in t he central nervous system. In the brain, angiotensinogen (AGT) is expressed in astrocytes and in some neurons important to cardiovascular control, but its functional role remains undefined. We generated a transgenic mouse enc oding the human AGT (hAGT) gene under the control of the human glial fibril lary acidic protein (GFAP) promoter to experimentally dissect the role of b rain versus systemically derived AGT. This promoter targets expression of t ransgene products to astrocytes, the most abundant cell type expressing AGT in brain. All transgenic lines exhibited hAGT mRNA expression in brain, wi th variable expression in other tissues. In one line examined in detail, tr ansgene expression was high in brain and low in tissues outside the central nervous system, and the level of plasma hAGT was not elevated over baselin e. In the brain, hAGT protein was mainly localized in astrocytes, but was p resent in neurons in the subfornical organ. Intracerebroventricular (ICV) i njection of human REN (hREN) in conscious unrestrained mice elicited a pres sor response, which was abolished by ICV preinjection of losartan. Double-t ransgenic mice expressing the hREN gene and the GFAP-hAGT transgene exhibit ed a 15-mm Hg increase in blood pressure and an increased preference for sa lt. Blood pressure in the hREN/GFAP-hAGT mice was lowered after ICV, but no t intravenous losartan. These studies suggest that AGT synthesis in the bra in has an important role in the regulation of blood pressure and electrolyt e balance.