The overall objective of the research is to evaluate the role of intracellularly occurring renin and angiotensin II in various tissues in the context of the pathogenesis of hypertension and in the regulation of blood pressure. The intracellular processing mechanism of renin in the kidney will be clarified. By comparing isoenzyme patterns in subcellular organelles of the kidney and secreted renin under different stimuli, we will delineate the roles of two different pathways of renin secretion from the kidney. Synthesis and function of renin and angiotensin in cells in extrarenal tissues will be investigated. Renin has been found in various tissues in coexistence with angiotensin II indicating local generation of angiotensin II. Subpressor concentrations of angiotensin II have been shown to contribute to hypertension by facilitating adrenergic transmission. We hypothesize that the angiotensin II locally generated in vascular tissues participates in the facilitation of the transmission. We will demonstrate the generation and release of angiotensin II from vascular tissues. The mechanism of regulation of the secretion of antiotensin II will be determined by identifying specific secretagogues. The secretion of angiotensin II from vascular tissues will be compared between spontaneously hypertensive rats and normotensive control rats to evaluate the role of vascular angiotensin II in the pathogenesis of hypertension. Mechanism of the local formation of angiotensin II will be clarified by identifying the origin of local renin and angiotensinogen in various extrarenal organs. Purified and isotope labeled angiotensinogen will be used to test the hypothesis of its endocytosis from plasma. The possibility of its local biosynthesis will be tested by identifying its mRNA and following de novo protein biosynthesis using radioisotope labeled amino acids. Mechanism of regulation of intracellular renin function will be evaluated by determining subcellular localization of renin and angiotensinogen. Intracellular function of renin in extrarenal tissues indicates a specific control mechanism for renin. Inhibited form of renin will be characterized and the presence of renin inhibitors will be determined. The intracellular renin inhibitor will be characterized. Newly devised techniques to be employed in these studies is expected to eliminate existing difficulties and will identify the role of intracellular renin-angiotensin systems in relation to the pathogenesis of hypertension and other endocrine regulation. This study will introduce a new view point to our search for the mechanism of blood pressure regulation and hypertension.
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