Diabetic nephropathy is characterized by significant derangements in the biochemical constituents of the glomerular basement membrane eg. heparan sulfate proteoglycan, sialic acid. Although these abnormalities are implicated in the pathogenesis of proteinuria, the underlying mechanisms are not known. Studies on pathogenesis of diabetic complications affecting other tissues eg. lens, peripheral nerves, have suggested an important role for alcohol derivatives of glucose i.e. sorbitol, myo- inositol (polyols). Agents that correct the abnormalities in polyol metabolism in these tissues have been shown to reverse their functional disturbances. We have successfully grown pure populations of cloned glomerular epithelial cells which express in vitro the characteristics of these cells in vivo eg. expression of heparan sulfate, sialic acid, collagen. We propose to test the hypothesis that abnormalities in the glomerular epithelial cell polyol metabolism are responsible for the derangements in glomerular HSPG metabolism and sialic acid content seen in diabetic glomerulopathy.
Our specific aims are: I. To determine the effect of altered medium concentrations of glucose and insulin on the rates of synthesis and catabolism of core protein and glycosaminoglycan moieties of heparan sulfate proteoglycan. II. Evaluation of mechanisms involved: To assess whether correcting insulin lack, preventing or reversing abnormalities in sorbitol and myoinositol rectify changes found in the synthesis and catabolism of heparan sulfate proteoglycan. III. (a) To study the effects of altered medium concentrations of glucose and insulin on the sialic acid content of the glomerular epithelia cells and on the overall cell surface electrical charge of the cells. (b) To investigate whether correcting (i) insulin lack (ii) abnormalities in sorbitol and myo-inositol rectify changes in sialic acid content and abnormalities in surface electrical charge. These studies will advance our understanding of the mechanisms underlying the abnormalities in the metabolism of biochemical determinants of glomerular permselectivity. This knowledge may pave way to design therapeutic strategies for diabetic nephropathy that causes enormous morbidity and mortality.
