The broad objective of this proposal is the analysis-of glomerular epithelial cell defects as pathogenetic factors in progressive glomerulosclerosis. This degenerative process of the glomerular capillary tuft is an important final common pathway that results in gradual loss of renal function in a variety of patients with renal disease and in many animal models of renoprival, immunological, and toxic injury. The process is often independent of the original insult and varies in intensity and time course from one individual to another both in humans and in the experimental animal. A better understanding of the mechanisms responsible for this type of glomerular damage should provide a more rational basis for therapeutic interventions aimed at arresting the destruction of the glomerular microvasculature. Although several hemodynamic and structural adaptations have been associated with progressive glomerulosclerosis, the precise cellular events and the pathogenetic mechanisms that result in occlusion of the microvasculature are at present unknown. A critical factor in this process is the damage co the integrity of the epithelial cell layer of the capillary wall, a condition that has been associated with size-selective permeability defects and accumulation of hyalin material which eventually occludes segments of the capillary tuft. It is hypothesized that the development of the highly differentiated visceral epithelial cell occurs during critical fetal and early postnatal phases of growth, and that this development is influenced significantly by dietary and growth stimuli that operate during this time. In the adult animal, the epithelial cell looses its capacity to replicate and relies exclusively on hypertrophy for subsequent physiologic or adaptive growth. The studies in this proposal are designed to investigate the cellular events that occur in this epithelium during the normal development of the kidney, under conditions of dietary restrictions during organogenesis, and following compensatory hypertrophy and other forms of capillary wall injury. The proposed investigations are aimed at establishing a correlation between qualitative or quantitative epithelial cell defects and progressive glomerulosclerosis following loss of functioning renal parenchyma. Autoradiographic, morphometric, and ultrastructural tracer techniques will be applied to well established animal models of human diseases that evolve with progressive proteinuria and glomerulosclerosis.
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