The kidney is a major site of insulin metabolism removing the hormone from the circulation by means of glomerular filtration and by extraction from the postglomerular peritubular circulation. Insulin removed binds to specific receptors in the apical and basolateral tubular membranes. Filtered insulin is internalized by endocytosis and degraded completely. However the role of receptors in mediating endocytosis, the intracellular pathway for insulin, and the contributin of lysosomal and extralysosomal compartments to the degradative process are poorly defined. Basolateral uptake form the peritubular circulation is also followed by degradation but it is not known whether internalization is a prerequisite. Indeed in contrast to the apical side of the cell, basolateral endocytosis is a minor process. The aim of this study are; 1) To evaluate the role of insulin receptors in mediating the renal uptake and degradation of insulin. 2) To characterize the intracellular pathways involved in the apical and basolateral uptake and degradation of insulin. 3) To characterize the products of insulin degradation and thereby to further our understanding of renal epithelial insulin metabolism. Studies will be conducted with kidneys from rats, and with cultured opossum kidney cell line and primary rabbit proximal tubular epithelial cells. Methodology includes subcellular fractionation, electron microscopic autoradiography, cell culture and high pressure liquid chromatography. These studies are particularly significant because of the major role played by the kidney in insulin metabolism. New information will be generated that should achieve our objectives of enhancing the understanding of renal insulin metabolism. In the long term, knowledge gained from this study should contribute significantly to our understanding of the physiology of insulin metabolism in general and in particular will form the basis of elucidating the pathophysiology of alterations of renal insulin metabolism that may occur in disease states.