Diabetic nephropathy is a complex and poorly understood complication of diabetes. While hyperglycemia is an important factor in its etiology, many aspects of the mechanisms by which poorly controlled blood glucose levels result in pathological changes to the glomerular cells are not known. One change that is observed in the glomerulus of diabetic rats is an increase in the production of eicosanoids. Phospholipase A2 (PLA2) cleaves phospholipids such as phosphatidylcholine at the sn-2 position of the glycerol backbone and liberates arachidonic acid, which is the precursor of eicosanoids. Therefore, changes in PLA2 activity can result in altered release of vasoactive eicosanoids from mesangial cells. This could dramatically alter the constrictor to dilator balance within the kidney leading to glomerular hyperfiltration. Glomerular mesangial cells contain receptors for agonists (e.g. ATP, bradykinin, vasopressin, EGF and endothelin) which have been shown to activate PLA2. Selected agonists that react with either G-protein linked or tyrosine kinase receptors will be used to investigate the effect of high glucose on PLA2 activity. Furthermore, the signal transduction pathways responsible for receptor- mediated activation of PLA2 will be investigated by examining the involvement of G-proteins and protein kinase C in receptor mediated activation of PLA2.
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