Sequential alterations in renal function occur in patients with diabetes mellitus which may be linked to, and in part mediated by, changes in glomerular PG synthesis. An increase in renal blood flow (RBF) and glomerular filtration rate (GFR) occurs early in diabetes and may play a key etiologic role in initiating the progressive decline in GFR later in the diabetic patient. The vasodilatory action of locally produced prostaglandins (PGs) on the renal vasculature and their ability to relax mesangial cells may contribute to the increases in RBF and GFR which occur early in diabetes. Moreover, glomerular PG synthesis may constitute an important compensatory mechanism in the later stage of diabetic nephropathy which helps to restore GFR nd RBF towards normal. Several lines of evidence also suggest that reduced renal PG synthesis may be one of many factors which contribute to hyporeninemia in diabetic patients. Earlier studies have suggested that alterations in phosphilipid composition and metabolism may have an impact on release of arachidonate (AA) and metabolism to PGs and lipoxygenase products. In this regard, release of AA from cellular phospholipids is often rate limiting for PG synthesis. The streptozotocin treated diabetic rat has been used extensively as a model for human diabetes and many of the changes in GFR, plasma renin activity and urinary PG excretion which have been described in diabetic patients have also been observed in the streptozotocin treated rat. Based on these cosiderations, we propose a series of studies to be conducted in glomeruli isolated from normal and streptozotocin diabetic rats which are aimed at examining a) the potential role of altered phospholipid content and metabolism in the expression of the biphasic changes in PG synthesis which occur in the streptozotocin diabetic rat (2 weeks, increase; 2 months, decrease) and b) the relationship of altered AA release and metabolism to PGs and lipoxygenase prducts to alterations in GFR and glomerular renin release in the streptozotocin treated rat. Studies will be conducted at 2 weeks and 2 months after streptozotocin treatment since biphasic changes in PG synthesis have been reported. The proposed studies should result in a more complete understanding of the factors and pathways governing AA release and PG synthesis in normal and diabetic glomeruli and the relationships between alterations in glomerular PG synthesis, GFR and renin release in early experimental diabetes.
