Patients with early diabetes mellitus exhibit marked abnormalities in renal function, including increased glomerular filtration rate, increased renal blood flow and decreased responsiveness to vasopressors such as angiotensin II. The glomerular mesangial cell plays an important role in the regulation of glomerular function. Cultured mesangial cells from diabetic animals produce an increased quantity and an altered profile of eicosanoids, notably an increase in prostacyclin (PGI2) production. In some tissues arachidonic acid metabolism is regulated by insulin. In the isolated rat adipocyte, PGI2 production is inhibited by insulin. In numerous tissues, glucocorticoids inhibit eicosanoid production. Glucocorticoids exert a permissive effect on vascular tone; when glucocorticoids are deficient, eicosanoid production is enhanced and responsiveness to vasopressors such as angiotension II is diminished. Therefore, functional renal abnormalities of early diabetes may be related to abnormal hormonal regulation of eicosanoid production by mesangial cells. Consequently, our objective is to study the effects of diabetes and insulin on arachidonic acid metabolism, especially on the production of PGI2 and PGE2, in cultured mesangial cells and other renal cells (e.g., glomerular epithelial cells) and in 3T3 L1 cells. We wish to determine the mechanism by which diabetes and insulin alter eicosanoid production and the role of lipocortin (present in great quantity in the cultured mesangial cell - see Preliminary Data) in the genesis of the abnormal eicosanoid production by the diabetic mesangial cell and other cells. We will study the effects of diabetes, insulin and glucocorticoids on eicosanoid production, lipocortin RNA content, ad lipocortin. We will test the hypothesis that insulin deficiency impairs the production and/or function of lipocortin so that the inhibitory effect of glucocorticoids is decreased or lost. Lipocortin will be measured by the Western blot technique, by radioimmunoassay and by assay of phospholipase A2 activity.
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