Local release of arachidonic acid and metabolism to biologically active eicosanoids in the region of the renal glomerulus may have profound influences on the overall function of the glomerular filtration unit. Some of the stimuli which lead to arachidonic acid release and further metabolism may be short lived while others induce changes in the resident glomerular cells which may be a profilerative nature and may produce irreversible changes in glomerular function and morphology. An understanding therefore, of the nature of the stimuli which initiates, biochemical, metabolic and morphologic changes in the renal glomerulus may give insight in potential points of regulation such that one may eventually be able to take advantage of the beneficial changes and eliminate the deleterious ones, in an attempt to preserve both short term and long term glomerular function. In this proposal, we would therefore like to explore the effects of protein synthesis inhibitors on the lymphokines IL-1, TNFalpha, and TNFbeta induced time dependent effects on PGE2 formation in the glomerular mesangial cell. We would then like to explore further the regulation of the enzymes along the arachidonic acid cascade particularly phospholipase A2 and cyclooxygenase induced by the lymphokines. Since there is synergy as our preliminary data suggest then we would like to evaluate the synergy or corporativity of the effects of the lymphokines on the growth factors PDGF, serum, and EGF on the functional activity or synthesis of phospholipase A2 and cyclooxygenase. These experiments will then be further extended to evaluate the biochemical events responsible for such synergy and evaluate at a cellular level the role of interleukin-1 and TNFalpha on PDGF synthesis and receptor regulation and the role of tyrosine kinase and other kinases on the IL-1 response in the mesangial cells. We will then like to evaluate the effectiveness of corticosteroids in modulating the effects of IL-1 on eicosanoid formation and the role of the oncogenes c-fos and c-jun in regulating these changes. Finally, we would continue the characterization of the phospholipase A2 we have purified from whole kidney cortex in an attempt to derive sequence in formation and generate antibodies which will then allow us to probe the regulation of this enzyme in response to a variety of lymphokines and/or growth factors.
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