Pathogenic factors causing diabetic glomerulosclerosis will be studied in experimental diabetic rats. The studies will include the effects of diabetes mellitus upon proteoglycan biochemistry including differentiation of basement membrane and matrix as well as cell surface matrix component associations. Since glomerular contractile properties are altered in diabetes, presumably effecting the glomerular cytoskeleton, calcium regulatory and response mechanisms will be studied using physiologic, morphologic and biochemical parameters. The response of the glomerular mesangium to injury, the mesangium representing a major target of diabetic glomerulopathy, will be examined using a non-specific inert chemical to initiate the injury, using several other factors such as high protein feeding and hypertension to simulate hemodynamic events which also add to the injury of the diabetic kidney. Since the kidney in nephrotic syndrome manifests biochemical changes of the glomerular filtration apparatus similar in some respects to what occurs in the diabetic kidney, proteoglycan metabolism and matrix protein interactions will be evaluated in two experimental models of the nephrotic syndrome. In an effort to extend known interrelations of matrix- and cell surface-related proteoglycans to cytoskeleton proteins, the fetal kidney in culture will be studied for modifications of development as a result of inhibition of either proteoglycan synthesis or cytoskeletal function at specific phases of development. Knowledge of those relationships and of their roles is important in determining fetal kidney development and growth. Finally, the effects of inhibition of polyol accumulation upon development of diabetic glomerulopathy will be studied by administering an inhibitor of a key enzyme in their synthesis measuring both physiologic and morphometric parameters which have been shown to be characteristic of diabetic glomerulopathy.
