Glomeruli, the filtering units of the kidney, are frequently involved in the course of immune inflammatory diseases of the kidney. Glomerular injury frequently includes focal or diffuse lesions that include cell necrosis, swelling and proliferation. Glomerular cells and/or infiltrating inflammatory cells may be responsible for this injury. Glomerular cells especially endothelial and mesangial cells are in close proximity to infiltrating inflammatory cells. We plan to explore if mediators released by glomerular cells or infiltrating inflammatory cells contribute to glomerular cell injury. We hypothesis that highly reactive oxidants and proteases released by leucocytes or tissue macrophages inflict injury to glomerular cells. We believe that this effect may range from membrane pertubation that alter glomerular cell responsiveness to various effectors, to advanced cell lysis and non-specific release of cytosolic constituents. Glomerular epithelial mesangial and endothelial will be incubated in vitro with enzymic sources of oxygen radicals and/or activated leucocytes and macrophages and their synthetic capacity of arachidonic acid products and responsiveness to known agonists will be determined. We will determine if the various glomerular cells respond differentially to the oxidants and if their susceptibility is dependent on differences in endogenous anti- oxidants. We will determine the effect of oxygen radical scavengers and inhibitors of proteinases on glomerular cell function. We will determine if changes in cytosolic calcium and metabolism of inositol phosphates accompany oxidant injury to glomerular cells. These studies will help understand biochemical mechanisms involved in glomerular cell injury. Alteration of glomerular cell metabolic activity and receptor function may ultimately alter glomerular filtration barrier and lead to increased glomerular premeability and eventually sclerosis. New strategies aimed at preventing or limiting glomerular injury may then become possible.
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