GLOMERULAR CAPILLARY WALL--NORMAL AND PATHOLOGIC

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Proteoglycans (PGs) are essential components of the extracellular matrices (glomerular basement membrane, GBM; mesangial matrix, MM), and apparently synthesized, in various proportions, by all the cell types o the renal glomerulus, i.e. epithelium, endothelium & mesangium. They impart charge- & size-selective properties to the glomerulus & maintain its integrity. Accordingly, structural derangements of the PGs, due to imbalance in their synthesis by different cell types of the glomerulus, would be expected to result in the disorganization of the extracellular matrices & proteinuria. Such structural alterations are seen in various immunologically & nonimmunologically mediated nephritides. We propose to delineate the pathogenetic mechanisms, relative to the proteoglycan biosynthesis, leading to such structural abnormalities by utilizing cell- biological biochemical, immunohistochemical & molecular biology techniques in the following four objectives: Objective I. cDNA probes for the rat GBM heparan sulfate-proteoglycan (HS- PG) will be prepared: following which nucleotide sequence determined & compared with the aminoacid sequence of the core-peptide of HS-PG. Objective II. Alterations in the proteoglycan biosynthesis at transcriptional & posttranslational levels will be investigated in immunologically & nonimmunologically-mediated glomerular nephritides by utilizing the above indicated techniques. Objective III. Effect of various inflammatory mediators, e,g., IL-I, PGA2, PGE2, TNF ROS; and glucocorticoids on the biosynthesis of PGs will be investigated in an organ perfusion system & by the techniques outlined above. Objective IV. Role of proteoglycans in renal glomerular development in vivo & in vitro states will be investigated by perturbing the metabolism at various steps of their biosynthesis with exposure to xyloside & puromycin. With these objectives we anticipate to delineate the breakdown in the cellular mechanisms & in the intricate balance of the biosynthesis of PGs by the various cell types of the glomerulus which lead to structural derangements in the extracellular matrices as observed in various nephritides.