Diabetes mellitus is the most common cause of renal failure in adults. Diabetic nephropathy characteristically produces structural and functional abnormalities in the glomerular mesangium which consists of mesangial cells and extracellular matrix. Cultured mesangial cells constitute a useful model system for the study of the role of the mesangium in glomerular pathophysiology. Mesangial cells synthesize and respond to cytokines such as interleukin I and platelet derived growth factor (PDGF). Recently, mesangial cells have been shown to possess receptors for insulin-like growth factor I (IGF I). We have identified IGF I and IGF I-binding protein(s) in culture medium from human mesangial cells. Our preliminary studies have also demonstrated that IGF I, in concert with other growth factors such as PDGF, stimulate DNA synthesis and that IGF I increases the abundance of mRNA for PDGF suggesting these two growth factors might interact in the regulation of mesangial cell proliferation. Moreover, our studies suggest that IGF I regulates matrix proteins since IGF I induces mRNA for Type I collagen, a form of collagen detectable in the extracellular matrix of diseased kidneys. Based upon these findings we hypothesize that IGF I acts as an autocrine factor in mesangial cells i.e. it is secreted by and acts upon these cells, and that these processes are regulated by factors produced locally or delivered by the systemic circulation. We further hypothesize that IGF I gene expression is abnormal in mesangial cells in the diabetic and that this abnormality plays a role in abnormal mesangial matrix production. Our studies are designed to elucidate the regulation of IGF I synthesis and secretion in cultured human mesangial cells and to elucidate the role of IGF I in the regulation of mesangial cell proliferation and extracellular matrix production. We will compare these results to those of cultured rat mesangial cells in selected experiments to provide the bases for interpretation of in vivo studies using the streptozotocin-treated rat model. We will examine IGF I gene expression in whole kidney tissue, isolated glomeruli and in mesangial cells by utilizing radioimmunoassay, Northern analyses, and in situ techniques. The long term goal of the proposed research is to elucidate the pathophysiology of diabetic nephropathy. These studies will enhance our general understanding of the mechanisms involved in the development of kidney diseases and will open the way for therapeutic applications of this knowledge.
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