Crescentic glomerulonephritis commonly causes permanent loss of renal function. The formation of the crescent requires a series of events beginning with immune/inflammatory cell damage to both structural elements and to glomerular cells. It progresses through a stage where fibrin is formed in Bowman's space to the accumulation of cells in Bowman's space (the """"""""crescent""""""""). Finally permanent damage is associated with production and cross-linking of collagen in both glomerulus and interstitium of the renal cortex. This progression of changes is the consequence of a complex series of interactions between intrinsic renal cells, fibroblasts, inflammatory cells and the immune system. From previous studies using experimental animals we know that the neutrophil, the macrophage and the coagulation system appear to be important elements in the sequence leading to crescent formation. We will further dissect the sequence of events by measuring the biochemical mediators produced by cells which are responsible for causing crescent formation and sclerosis. We will focus on four important areas which we need to understand. These will be: (a) mechanisms of basement membrane damage by enzymes and oxidants from phagocytic cells, (b) macrophage function, monokines and eicosanoids, (c) regulation of glomerular procoagulant and fibrinolytic signals, and (d) regulation of collagen formation and growth factors. We will use a model of anti GBM disease in the rabbit which reproducibly causes crescent formation together with cultured renal cells, isolated inflammatory cells and an in vitro human anti GBM system to examine these questions. This combination of a team of committed, experienced individuals working closely together but from different perspectives will produce new and useful information about how and why crescents form, what biochemical signals are important and therefore what might be done to stop the progression to collagen formation that causes permanent renal failure.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Diabetes and Digestive and Kidney Diseases Special Grants Review Committee (DDK)
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University of Michigan Ann Arbor
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Ann Arbor
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