The long term goal of the project is to define and characterize mechanisms responsible for the intrarenal, hormonal microcirculatory and transport derangements in angiotensin II(AII)-dependent hypertension. Dr. Navar has confirmed and extended a very interesting observation that the renal proximal tubule fluid concentration of AII is very high There are 7 specific aims: 1) To characterize how A-I and AII are secreted into the proximal tubular fluid and determine the role of luminal AII in the autocrine proximal reabsorption rate in normal and hypertensive rats. 2) Evaluate the hypothesis that increased circulating AII enhances intrarenal formation of AII through a renin independent mechanism. 3) Determine the effects of AII infusion on tubuloglomerular feedback mechanism and identify the counteracting factors that influence the sensitivity of the tubuloglomerular mechanism in the kidney of AII infused rats and non-clipped kidney of 2K1C hypertensive rats. 4) Evaluate the contribution of enhanced renal sympathetic activity to the AII induced increases in intrarenal AII in 2K1C and AII infused rats. 5) Delineate the mechanism responsible for the differential effects of ACE inhibitors and AII receptor antagonist on renal hemodynamics and sodium excretion in 2K1C and AII-infused rats. 6) Evaluate the microcirculatory derangements that lead to altered vascular reactivity in non-clipped kidneys of 2K1C rats and in kidneys of AII infused rats. 7) Determine the intrarenal localization of enhanced intrarenal formation of AII and the changes in AT1 receptors and their mRNA and investigate the molecular mechanism responsible for providing a sustained source of A-I under conditions where renin and renin mRNA are suppressed.
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