Evidence from multiple sources has strengthened the cardinal significance of the intrarenal renin-angiotensin system in the pathophysiology of hypertension. Through its synergistic influences on renal microcirculatory and epithelial transport processes, angiotensin II (ANG II) exerts powerful hypertensinogenic influences when its level of activity is inappropriately elevated for the co-existing physiological status. The long term objectives of this project are to delineate the mechanisms responsible for the regulation of intrarenal ANG II levels, and its compartmentalization, and to elucidate the functional consequences of augmented intrarenal ANG II levels. Of particular significance is the demonstration that a kidney exposed to sustained elevations in circulating ANG II undergoes progressive augmentation of intrarenal ANG II, in spite of renin depletion. The data obtained during the current project period have led to the hypothesis that increases in circulating ANG II lead to augmented intrarenal ANG II levels via receptor mediated internalization of ANG II into protected compartments which compound the maintained intrarenal ANG II production. We have also demonstrated that ANG II and/or its precursors are secreted by proximal tubule cells into the tubule fluid. For the next period of support, experiments will be performed in normal and hypertensive rats and in specific gene targeted mice to determine the mechanisms responsible for the proximal tubular fluid ANG II levels and establish the unique role of intraluminal ANG II in the autocrine regulation of proximal reabsorption rate in normal and hypertensive states. We will also investigate the mechanisms responsible for the ANG II-induced augmentation of intrarenal ANG II content and the sites of intracellular ANG II accumulation in order to delineate the relationships between mechanisms responsible for sustained intrarenal ANG II production and those responsible for AT1 receptor dependent uptake of ANG II. Functional studies will characterize the alterations in the tubuloglomerular feedback mechanism and afferent arteriolar autoregulatory responsiveness caused by ANG II-induced augmentation of intrarenal ANG II. The results obtained from the proposed studies should provide important new information regarding the mechanisms underlying the renal functional derangements in ANG II-dependent hypertension.
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