This grant application is to continue studies on the tissue renin- angiotensin system in hypertension. The hypothesis of this proposal is that gene expression of components of the renin-angiotensin system in localized tissues is altered in different models of hypertension independently of circulating angiotensin. and that the tissue angiotensin contributes to high blood pressure. The techniques of molecular biology and in situ hybridization, combined with direct measurements of renin- angiotensin components, will be used to test the hypothesis. One of the advantages of studying mRNA accumulation in such models is that multiple tissues can be collected in the animals at the same time.
Six aims are proposed. First, tissue mRNA expression in different models of hypertension will be studied, using northern blot analysis. Probes for angiotensinogen, renin and converting enzyme will be applied, and brain, vasculature, kidney, liver, adrenal, heart and skin will be tested in one- kidney-one-clip, two-kidney-one-clip, DOCA-salt, SHR and Dahl salt- sensitive hypertensive rats and their controls.
The second aim, once the pattern of tissue mRNA has been established, will be to study gene expression during the development of hypertension to test if the expression appears before blood pressure elevates or if it is a result of hypertension. In the third aim the technique of in situ hybridization will be used to locate with microscopic precision were changes are occurring in different areas of the brain and autonomic ganglia.
The fourth aim i s to measure levels of angiotensins and other components of the synthesis in order to test whether the mRNA accumulation represents increased synthesis.
Aim five is to define the cellular localization of the mRNA, particularly in neurons versus glial cells of the CNS and sympathetic nervous system, and also endothelial cells nad LLCPK1 cells.
Aim six is to study the regulation of gene expression suing hormones associated with stress. Also, angiotensin II will be tested for its role in negative feedback of mRNA expression. Studies will be carried out both in vivo and in vitro. The expression of mas-oncogene mRNA in response to angiotensin II will be studied. The goal of the project is to focus on the locus of tissue angiotensin gene expression which contributes to the development of hypertension.
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