The proposal attempts to integrate the roles of circulating factors such as hormones and immunecomplexes with locally generated responses and mediators in the control of renal function. Circulating agents will include vasoactive hormones, and IgG complexes. Local mediators encompass eicosanoids, platelet activating factor and cytokines. The long-term objectives are to expand our understanding of the cellular mechanisms involved in the regulation of glomerular function in the kidney and their contributions to glomerular disease. This will be essential for the rational design of therapeutic interventions for kidney diseases. Two major specific aims are envisioned: 1) To elucidate the interaction of IgG complexes, vasoactive agents, autacoids, and cytokines with mesangial cells and the resulting consequences on mesangial cell biology in order to understand their roles in glomerular physiology and pathophysiology. 2) To determine the cellular mechanisms by which the above agents influence mesangial cells. In order to achieve these goals, we will use cultured mesangial cells, J774 macrophages, and S49.1 T cells. We have identified a specific Fc receptor for IgG on rat mesangial cells. We will now examine factors controlling the expression of the Fc receptors using binding studies, immunoprecipitation, Northern blotting, and in situ hybridization with specific cDNA and RNA probes for the Fc receptor. These studies will then be expanded to in vivo studies to evaluate the Fc receptor function in vivo. We will also examine the consequences of Fc receptor occupancy on mesangial cells. This will be accomplished by determining phospholipid turnover, arachidonic acid metabolism inositol phosphates, cyclic nucleotides, cell proliferation and cytokine generation matrix production. Overall, the proposed studies represent an extension of our current research on the biology of the glomerular mesangial cell and their control mechanisms in the context of glomerular function in general.
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