The primary focus of this proposal is to study in animal models of glomerular injury the interrelationship between site of injury, the determinants of glomerular ultrafiltration and the processing of macromolecular proteins through the mesangium. For this purpose we propose to study models of renal disease in which the principal site of injury is the glomerular mesangium or the glomerular capillary loop. In addition, we propose to evaluate mechanisms of proteinuria in those glomerular diseases characterized by proteinuria. In these latter studies, measurements of the permselective nature of the filtration barrier can be performed utilizing physiological techniques to discriminate size and charge characteristics of the filtration barrier and correlate these findings with an assessment of glomerular polyanion. The studies of glomerular function will include whole kidney and single nephron measurements. In particular, the pressure and flow determinants of glomerular ultrafiltration will be measured. The permeability of the filtration barrier will be studied by dextran and dextran sulfate clearances, as well as by morphologic evaluation of glomerular polyanion. The results of these functional and morphological studies will then allow an integrated approach to the study of the uptake and processing of macromolecules by the glomerular mesangium. Although the glomerular mesangium is not accessible to micropuncture techniques, kinetic uptake and egress studies can be performed utilizing macromolecular probes. It has been demonstrated that hemodynamic factors and the permeability characteristics of the glomerulus can effect the kinetics of macromolecular processing through the mesangium. The proposed experiments are designed so that the kinetic studies of macromolecular protein in the mesangium will coincide with our physiological and morphological studies and therefore allow for a holistic interpretation of the experimental data.