The renal glomerulus is a major target in a variety of inflammatory diseases of the kidney. One of the major cell types involved in these processes is the mesangial cell. The release of bioactive molecules within the glomerular unit may influence GFR and renal plasma flw by altering the contractile tone of the renal mesangial cell. In addition lymphokines such as IL-1Beta may up regulate a variety of genes encoding proteins which may generate bioactive molecules which are toxic to the glomerular filtration unit, may be chemotactic to leukocytes and may lead to the elaboration of a number of extracellular matrix proteins which may contribute to glomerular obsolence. Many of the genes up regulated by IL- 1beta are mediated by transcriptional mechanisms. However there are a subset of important pro-inflammatory genes represented by the inducible cyclooxygense (Cox-2) and the inducible nitric oxide (iNOS), which generate prostaglandins and nitric oxide respectively, which are subject to post-transcriptional regulation. The mechanisms by which this regulation occurs is not well understood. We plan to address these issues by demonstrating that these messages carry cis-acting elements by utilizing functional assays of chimeric reporter genes and electromobility shift assays. Finally, we will attempt to define the mechanisms by which trans-acting factors suppress or facilitate translational efficiency and destabilization of mRNA and if these proteins are regulated through phosphorylation mediated by the MAPK family of kinases. An understanding of these intracellular events are important in understanding the cellular response to injury.
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