The ability of the brain to synthesize angiotensinogen, angiotensin I and angiotensin II is now well established and it is widely accepted that angiotensin I and II produced by the brain itself can affect neuronal activity, autonomic function and various behaviors, most prominently thirst and sodium appetite. The brain circuitry involved in cardiovascular homeostasis is clearly affected by both circulating angiotensin II (via its action on circumventricular organs) and by the activity of the brain's own angiotensin system. Some evidence also suggests that an increase in the activity of the central angiotensin system is one of the factors involved in the resetting of the homeostatic regulation of arterial pressure (and blood volume) to higher levels in various forms of experimental hypertension. Yet on a cellular level, the reality of the central angiotensin system(s) remains obscure. Unlike classical peptide euromodulators, the prohormone angiotensinogen is reportedly found at 100-fold molar excess over the active hormone, angiotensin II (Ang II), is present extracellularly and may be synthesized by glia or the microvasulature as well as by neurons. Morever, the enzymatic processing of angiotensinogen in the brain is quite controversial with regards to the nature of the protease that releases brain angiotensin. It is also not known whether brain angiotensinogen gene expression varies in response to physiologic status. The purpose of the proposed research is therefore to use a molecular biologic approach to resolve a specific set of issues concerning the cellular site of synthesis of brain angiotensinogen, angiotensinogen gene expression in the brain during hypertension or changes in blood osmolarity and the nature of the brain angiotensinogen processing enzyme. It is proposed to use our angiotensinogen cDNA to determine what brain cells (neurons, glia) synthesize central angiotensinogen. In addition, sites of brain angiotensinogen accumulation will also be determined after development of anti-angiotensinogen sera. Brain isorenin will be described by isolating and characterizing its cDNA. The role of the angiotensin system in hypertension will be explored by quantitating brain angiotensinogen mRNA accumulation in individual nuclei in the spontaneously hypertensive rat and its normotensive control rat. Changes in brain angiotensinogen gene expression will also be examined as a function of changes in blood osmolarity. The results of these studies will significantly advance the state of knowledge in this field.
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