Many kidney diseases are characterized by relentless progression to end-stage renal failure. Sometimes, this progression is the result of continued activity of the initiating event. In many instances, the pathway to glomerular destruction involves poorly understood mechanisms. Putative mechanisms include glomerular hyperfiltration and hypertension, mesangial accumulation of serum-derived macromolecules, and activation of intraglomerular coagulation. Exactly how these possible mechanisms lead to the observed functional and structural deterioration are unclear. It is, however, generally accepted that a number of potent biological molecules participate in these processes. These molecules include lipid-derived mediators such as cyclooxygenase and lipoxygenase metabolites of arachidonate, platelet activating factor, epidermal growth factor (EGF), platelet-derived growth factor (PDGF), transforming growth factor beta (TGF-B), angiotensin II, and interleukin-1. This Center Grant utilizes parallel techniques in physiology, pathology, pharmacology, biochemistry, cell biology, and molecular biology to define the specific mechanisms leading to glomerular and tubular dysfunction and progressive glomerular destruction. Multiple experimental techniques are applied to specific disease models representing two general categories: non- immunologic including renal mass ablation, puromycin- aminonucleoside nephrosis and adriamycin toxicity and immunologic, namely, renal allograft rejection. Standard glomerular micropuncture, as well as the newly developed technique of serial glomerular micropuncture allows for functional characterization of the disease process at varying time intervals. Morphologic quantitation of glomerular injury will be correlated with measurements of glomerular function. In vitro examination of glomerular preparations as well as cultured glomerular cell types will elucidate the roles of important biologic mediators in producing the functional and structural changes. Matrix compositions of sclerosing glomeruli will be defined and regulation of mRNA for matrix synthesis will be assessed via in situ hybridization techniques. The role that biologically important mediators play in altering epithelial cell functions will also be examined utilizing the in vitro tubule perfusion. The investigators in this program represent a unique blend of disciplines and sophisticated techniques that can be focused on one of the highest priority questions in kidney disease, i.e. the pathogenetic mechanisms leading to progressive nephron destruction.
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