The remnant kidney (RK) model (5/6 reduction in renal mass) has been proposed as the experimental model for progressive nephron loss observed in many human diseases. Based on the morphologic characteristics of glomerular injury and the demonstration of impaired renal autoregulation in this model, we have proposed that progressive glomerular sclerosis is a consequence of hypertensive injury to an """"""""unprotected"""""""" microvasculature, despite the moderate severity of systemic hypertension (HTN). The proposed investigations are designed to further delineate the mechanisms responsible for the increased vulnerability of renal microvasculature to hypertensive injury after reduction in renal mass. The first set of experiments will test the hypotheses that (1 impairment of renal autoregulation results in pathogenetically significant transmission of acute exacerbations of moderate systemic HTN to glomeruli and (2) the impact of transmitted pressures, both ambient and during acute exacerbations, is further magnified by glomerular capillary hypertrophy (Laplace Law: Tension = Pressure x Radius). These studies will be performed at 4 weeks after ablation in Munich-Wistar rats at which time omega 90% have developed moderate systemic and/or glomerular HTN, yet only omega 30% of the rats exhibit morphologic injury. In each individual rat, AP will be continuously monitored by telemetry to quantitate the frequency and duration of acute episodes of HTN; glomerular pressures (PGc) will be measured in the ambient state and after experimental increases in AP to obtain peak values corresponding to the episodes of acute exacerbations of HTN; mean glomerular capillary radii will be measured morphometrically to calculate ambient and peak glomerular capillary wall tension values. These parameters of systemic and/or glomerular HTN will be correlated with morphologic glomerular injury in individual rats by multivariate analysis. The second set of experiments will define the time course and distribution of glomerular and microvascular injury after controlled exposure of remnant kidneys to systemic HTN with chronic servo-null controlled aortic occluder. These investigations will provide insights into the mechanisms responsible for the well established adverse consequences of systemic HTN on the course of coexistent renal disease. Additionally, these studies will define the parameters of adequate blood pressure control that is required in order to prevent progressive nephron loss when functional renal mass is reduced.
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