Immune-mediated glomerulonephritis is characterized by an invasion of macrophages into the glomerulus, and enhancement in glomerular lipid mediator production, and renal dysfunction. Evidence suggests that macrophages and lipid mediators are critical components of the renal in jury. Essential fatty acid (EFA) deficiency, which leads to a decrease in arachidonate and its replacement with the abnormal fatty acid, 20:3(n-9), has proven to be a uniquely valuable tool to probe the role of macrophages, attenuates the changes in glomerular lipid mediator production, and prevents the renal dysfunction. In consequence, it is hypothesized that lipid mediators play a crucial role in glomerulonephritis, mediating the influx of macrophages and the consequent renal functional alterations. The protective effect of EFA deficiency is conjectured to result from an interference with macrophage elicitation and an inhibition of lipid mediator production. Specific goals of the project are thus to determine the synthesis and cellular source within glomerulonephritis and how their elaboration is affected by EFA deficiency. Studies will also address whether EFA deficiency affects macrophage functional responses relevant to inflammation such as chemotaxis, adherence or activation. Ongoing efforts to isolate the mediator responsible for macrophage elicitation in glomerulonephritis will be continued. Immunologic and pharmacologic agents will be used to dissect out the role of both resident and elicited glomerular macrophages in the observed metabolic and functional alterations. Attempts will be made to develop dietary and/or pharmacologic strategies to reproduce the salutary effects of EFA deficiency in glomerulonephritis. Experiments will also address the underlying cellular and biochemical mechanisms of the changes in glomerular lipid mediator production in nephritis. The ultimate aim of the project is to develop strategies to treat glomerulonephritis that avoid the toxicity of current therapy (i.e non-specific immunosuppression). Because glomerulonephritis can also be thought of as a general paradigm for immunoinflammatory disorders, it is hoped that the results derived from this study will be applicable to other disorders such as autoimmune diabetes, myocardial infarction, or rheumatoid arthritis.
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