The proposal attempts to integrate the roles of circulating hormones and that of locally generated mediators including prostaglandins, lipoxgenase products and platelet activating factor in the function of the kidney. The questions to be examined include: 1. What is the exact mechanism by which some hormones stimulate arachidonic acid release? 2. How does this phenomenon relate to the effect of these agents on cell function? 3. Are some of the effects mediated by calcium-phospholipid-dependent protein kinase and, if so, which are the cellular substrates? 4. What is the role of lipoxygenase products on glomerular function and how is their synthesis controlled? 5. Do glomeruli and glomerular cells produce platelet activating factor, and if so is this synthesis altered in renal disease? The tissues to be studied will include: isolated glomeruli, culture of glomerular cells, toad urinary bladder, and isolated collecting tubules. The mechanism of action of vasoactive hormones, e.g. angiotensin II and vasopressin, will be examined in these tissues. Physiological parameters will include contraction of cells and transport of water and solutes. In parallel biochemical events will be determined: phospholipid turnover, arachidonic acid release, synthesis of prostaglandins and lipoxygenase products, synthesis of platelet activating factor (a lipid mediator), cAMP generation, various protein kinases and their endogenous substrates, etc. Identification of the role and mechanism of action of diverse, but interconnected lipid modulators with circulating hormones in vitro should improve our understanding of their in vivo contribution to the physiology and pathophysiology of the kidney. This knowledge will then permit the design of specific therapeutic avenues to glomerular diseases and disorders of the urinary concentrating mechanism.
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