BIOLOGY OF PROGRESSIVE NEPHRON DESTRUCTION

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A number of risk factors for progression of renal disease have been identified and there has been a major effort on the part of many investigators to elucidate the important mechanisms and key mediators responsible for progressive nephron destruction. The list of mechanisms and potential mediators is large. We have chosen to explore the central role that the enzyme, cyclooxygenase, and its products may play in progressive nephron destruction for a number of reasons. First, there is ample evidence that many of the postulated mechanisms and certainly the majority of the proposed peptide mediators of progressive renal damage are intimately intertwined with cyclooxygenase product formation in certain regions of the kidney. Second, there is evidence from the relatively crude maneuver of cyclooxygenase inhibition that in diseased kidneys, cyclooxygenase products may be either beneficial, as in the case of preserving renal blood flow (is this beneficial in the long run?) or detrimental, as in the case of proteinuria which can be reduced in magnitude by cyclooxygenase inhibition. Third, critical tools necessary to address the cyclooxygenase pathway are now available and, indeed, some have been developed by participants in this Center. Quantitation and structural verification of product formation, evaluation of cyclooxygenase enzyme activity and its regulation at the genetic level, molecular characterization of the effects of cyclooxygenase products on extracellular matrix proteins, and other approaches proposed in this Center grant are necessary to define what is likely to be a central role for cyclooxygenase and its products in the progression of renal disease. Developments in the molecular biology of eicosanoid receptors and developments in the pharmacology of specific agonists and antagonists will make available ways to intervene. This Center is composed of four projects and four cores, one being administrative and three being scientific. In exploring the link between cyclooxygenase and its metabolites of arachidonic acid with progressive renal disease, this Center proposes a broadbased in vivo and in vitro approach to both immune and non-immune models of progressive nephron destruction. In vivo and in vitro functional studies, biochemical studies, and molecular biologic approaches are all planned. Project #1 focuses predominantly on the role of cyclooxygenase and arachidonate metabolites of this enzyme in models of inflammatory and non-inflammatory immune injury in the rat kidney. Project #2 focuses on both in vivo and in vitro examination of progression in the remnant kidney model providing insights into the role of cyclooxygenase. Project #3 is exclusively an in vitro project focusing on glomerular endothelial, and visceral epithelial cells. Finally, Project #4 focuses on the tubule in the remnant kidney model. The three scientific cores interact with all four of the projects providing analytic support for arachidonate metabolite measurements and structural verification, structural and quantitative morphometry support, and support in the biochemical and molecular characterization of extracellular matrix components. We believe that the investigators in this Center represent a powerful and unique blend of techniques and interests that will be focused on a very important issue, i.e. the role of cyclooxygenase metabolites of arachidonic acid in progressive nephron destruction.