Angiotensin II (Ang II), a physiologically active octapeptide, plays an important role in cardiovascular homeostasis as well as renal and electrolyte regulation. This peptide induces diverse responses, some occur immediately but others such as the regulation of gene expression and modulation of growth, are delayed considerably. Many short term effects elicited by Ang II are associated with transmembrane signal transduction mechanisms. Evidence is accumulating which suggests that Ang II may also have a direct nuclear effect. This nuclear action may account, at least in part, for some of the delayed, long term effects of Ang II. The overall goal of this proposal is to study the mechanism of the nuclear effect at the molecular levels. We have shown the presence of specific, saturable Ang II receptors in the nuclei of liver cells. These receptors will be characterized in greater detail by determining the specificity of binding of various angiotensin fragments and analogous. These characteristics will be compared to those of the plasma membrane Ang II receptor to determine if the nuclear receptor is similar or if it represents a new binding protein. Once we have characterized the nuclear receptor, a study of the regulation of this receptor will then be initiated. Perturbations which are known to regulate the plasma Ang II receptor will be employed to determine if the plasma and nuclear receptors are regulated in parallel. We will then purify this receptor using standard chromatographic techniques. To determine the mechanism of action of this receptor, the interaction of Ang-nuclear receptor complex with genomic DNA will be investigated using the regulatory regions of the renin gene as a model system. The sequence necessary to confer angiotensin responsiveness to a gene will be determined using molecular biological techniques. The results of these studies should greatly increase our knowledge of the mechanism of action of this important peptide and should further increase our understanding of peptide hormones in general.
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