In angiotensin (Ang) II dependent hypertension, Ang II exerts powerful hypertensinogenic influences on intrarenal microcirculatory and transport processes eventually leading to renal injury, proliferation and fibrosis. Chronic elevations in Ang II lead to increases in intrarenal and interstitial Ang II, AT1 receptor mediated uptake of Ang II into endosomes and augmentation of intrarenal angiotensinogen (AGT) and tubular renin mRNA and protein via AT1 receptor mechanisms. This leads to increased AGT secretion into the proximal tubule and spillover into distal nephron segments as manifested by urinary excretion rate of AGT which is closely correlated to kidney Ang II content. AGT in distal nephron segments coupled with stimulation of collecting duct renin may result in augmented distal Ang I and Ang II levels. For the next period, efforts will be focused on mechanisms responsible for the regulation of intratubular Ang II concentrations and on delineation of the interactions between intraluminal and interstitial Ang II to the autocrine regulation of proximal tubule and distal reabsorption rate. We will assess the consequences of AT receptor mediated internalization of Ang II on the enhanced intrarenal production of AGT. We will distinguish between the effects of increased AT1 receptor stimulation and the effects of elevated arterial pressure, per se, in mediating the augmented intrarenal AGT and renin mRNA and protein and urinary AGT excretion rates. Functional studies will determine the augmented distal tubular sodium and fluid reabsorption occurring in Ang II dependent hypertension. We will also determine the compensatory role of the intrarenal heme-hemooxygenase-carbon monoxide system to the derangements that occur in Ang II dependent hypertensive rats. The possible interactions between intrarenal Ang II and renal interstitial ATP in mediating altered hemodynamic and transport function as well as the early proliferative responses in Ang II dependent hypertension will be evaluated. In vivo experiments performed on hypertensive rat models including the Ren2 TGR rats and gene targeted mice will utilize renal clearance, micropuncture, microperfusion and microdialysis procedures. In vitro experiments will utilize the blood perfused juxtamedullary nephron preparation and cultured cells. Physiological experiments will be complemented by analysis of plasma, kidney and tubular fluid contents of Ang II, ANG I, renin and AGT. The results obtained will further enhance our understanding of the important role of the intrarenal/intratubular/ interstitial renin angiotensin system in the pathophysiology of Ang II dependent hypertension.
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