Following the reduction of renal mass, adaptive alterations in both glomerular and tubular functions occur in surviving nephrons. There is increasing recognition that such adaptation exerts injurious effects, and provide pathways for progressive nephron damage. The cellular and molecular events arising out of these adaptive processes, which culminate in renal injury, are poorly understood.
The aim of this revised research proposal is to explore the role of three well defined humoral systems in adaptation and injury in the glomerular microcirculation following the loss of renal mass, with special emphasis on glomerular hemodynamic alterations. First, we will investigate whether augmented synthetic rates of both the vasodilatory and vasoconstrictor prostanoids, which we have recently described in the remnant nephron, determine the pattern of hemodynamic response of the remnant microcirculation to alterations in perfusion pressure. We will examine the dependency of the renal functional reserve of the subtotally nephrectomized kidney on the capacity for vasodilatory prostaglandin synthesis. We will characterize the functional effects of augmented thromboxane synthesis on the glomerular microcirculation of the remnant kidney and examine whether such increased production of thromboxanes lead to alterations in permselectivity. These functional studies would be coupled with studies examining the humoral mechanisms underlying augmented prostanoid synthetic rates. Secondly, we will explore the role of platelet derived growth factor (PDGF) as a mechanism by which alterations in glomerular hemodynamics lead to glomerular sclerosis. We hypothesize that the heightened pressures and flows of the glomerular microcirculation lead to injury to the capillary endothelium thereby inducing the adhesion of platelets, subsequent aggregation, and discharge of PDGF into the surrounding tissues. We further hypothesize that in view of the well established role of PDGF in promoting vascular injury, such heightened release of PDGF may represent an important mechanism for ongoing glomerular injury in surviving nephrons. Finally, we will explore the role of the complement system in determining the alterations in glomerular hemodynamics and permselectivity that attend reduction of renal mass, with a special emphasis on the complement components, amidated C3 and the terminal attack complex, C5b-9. The mechanism of ammonia triggered, complement mediated tissue injury as a pathway by which the level of dietary protein intake dictates the severity of renal injury will also be explored. In summary, these studies would provide greater insights into the role of these humoral systems in adaptation and injury in surviving glomeruli and hopefully would suggest therapeutic measures by which the progression of renal disease can be retarded.
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