NEURAL-VASCULAR ANGIOTENSINS--ALTERATIONS IN SIGNAL TRANSDUCTION

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The focus of this project is to determine whether tissue-specific increases in angiotensin (Ang) peptides alter Ang peptide receptors or their mechanisms of signal transduction. A genetic model of high blood pressure will be used--the transgenic (TG) rat which contains the mouse Ren-2 gene. In this model, plasma renin is not elevated, suggesting that the hypertension is to due to activation of the circulating renin- angiotensin system (RAS). However, the elevated blood pressures in TG rats can be reduced by angiotensin converting enzyme (ACE) inhibitors or the AT1 receptor antagonist losartan, implicating the participation of the RAS in the hypertensive process. Although circulating levels of Ang peptides were not elevated in TG rats compared to controls rats, the brains of TG rats contained higher levels of Ang I, Ang II and Ang-(1-7). Furthermore, treatment of TG rats or SHRs with ACE inhibitors elevates Ang-(1-7) levels and decreases the density of Ang receptors in the brain, in agreement with alterations in Ang receptors following ICV infusions of Ang peptides. In addition, our previous results have shown that Ang- (1-7) can be generated by tissue specific processing pathways and that Ang-(1-7) activates distinct signalling pathways. Our hypothesis is that the tissue-specific expression of the Ren-2 transgene results in elevated local production of Ang peptides which alter expression of Ang peptide receptors or their activation of select signalling pathways. The proposed studies focused on the cellular components of two tissue RAS-- the central RAS present in brain areas which participate in control of cardiovascular function as compared to the vascular RAS contained within the wall of the blood vessel, since previous studies have shown that Ang II receptors and their signal transduction mechanisms are altered in both the brain and vasculature of the SHR. To determine whether Ang peptide levels are elevated by the expression of the transgene, renin mRNA, renin activity, Ang peptide levels and Ang processing enzymes will be measured in cells from T G rats versus their negative littermates. Ang peptides receptors and their activation of specific signalling pathways in cells from TG rats will be compared to cells from their normotensive littemates. Finally, the effects of chronic elevated levels of Ang peptides as may occur endogenously in the rat, and of various peptidase inhibitors or receptor antagonists which interfere with the RAS, on Ang peptide receptors and signalling pathways will be studied in vitro, in isolated cells.