Major developments in glomerular research during the last five years have been the clarification of the role of charge in glomerular filtration, the discovery that proteoglycans play a role in glomerular permeability, the discovery of new basement membrane components, and the clarification that the pathogenesis of Heymann's nephritis involves fixed glomerular antigens. Our interest has centered for some time on defining the structural basis of glomerular filtration and the structural basis of abnormal filtration that occurs in various glomerular diseases. During the previous grant period we have: a) identified and characterized the anionic sites composed of heparan sulfate proteoglycans in the GBM; b) demonstrated that heparan sulfate proteoglycans play a role in establishing the permeability properties of the GBM; c) studied the differentiation of glomerular anionic sites in the newborn rat; and d) the nature of the GBM-cell attachment; e) determined that the laminae rarae of the GBM have a different composition from the lamina densa; f) identified and purified the Heymann nephritis antigen (gp330); and g) localized gp330 in coated pits of the glomerular and proximal tubule epithelium. During the next grant period we intent to pursue these problems further and have defined 5 main problem areas in which to concentrate our efforts: 1) to isolate, characterize and localize subpopulations of glomerular proteoglycans using specific antibodies for immunochemical studies; 2) to determine the determine whether or not the mechanism of immune complex binding to coated vesicle antigens in Heymann nephritis applies to other epithelial antigens; 4) to determine the nature of the changes in epithelial sialoglycoprotein(s) that occurs in aminonucleoside nephrosis; 5) to determine by high resolution scanning and transmission electron microscopy and refined immunocytochemical techniques the composition of various GBM components. A number of experiments designed to gain insights into these problems are proposed.
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