We propose to study the relationship among glomerular epithelial cell (GEC) injury, proteinuria and glomerular sclerosis in rats. Since glomerular scarring occurs in many human glomerular diseases, we will address this problem in experimental proteinuric states which develop glomerular sclerosis. The critical role of chronic proteinuria in the pathogenesis of GEC injury will be studied in hyperalbuminemic (overload) proteinuria by extending the proteinuric phase from four to 28 days. GEC structure will be evaluated by light and electron microscopy, and GEC endocytic function will be determined by studying the kinetics of the disappearance of protamine-heparin aggregates (PHA) from the lamina rara externa of the glomerular basement membrane. In prior studies we have correlated decreased disappearance with the onset of proteinuria in autologous immune complex nephritis and aminonucleoside nephrosis. To further define the role of GEC endocytosis in the pathogenesis of proteinuria and the relation of GEC injury to glomerular scarring, we will study GEC structure and function in experimental models with defined pathogenetic mechanisms. Thus, we will study the effect of glomerular injury in Adriamycin nephrotoxicity (presumed drug-induced free radical injury) and extreme ablation ofrenal mass (glomerular hyperfiltration) upon GEC structure and PHA disappearance. We will attempt to differentiate between a primary GEC endocytic defect and abnormal lysosomal function by analyzing the lysosomal enzyme content of the GEC in all three experimental conditions. Finally, we will determine the relationship between these glomerular diseases and glomerular scarring by inducting the experimental diseases, following the rats renal function and protein excretion, and studying GEC morphology. Based upon our previous studies and observations on chronic proteinuric states in humans, we believe that GEC injury, proteinuria and progressive glomerular sclerosis are related. It is our goal to define this relationship in experimental animals and to apply this knowledge to our understanding of progressive glomerular disease in humans.
