Glomerular immune injury underlies the development of progressive renal failure in nearly one half of patients with end-stage renal disease. The biology of progressive nephron destruction during glomerular inflammatory injury is complex. It involves complement-mediated cellular toxicity, leukocyte and platelet activation, the local release of peptide and lipid- derived autoacoids and growth factors, free-radical-induced lipid peroxidation, and altered glomerular dynamics. In concert, these mediator pathways lead to impairments in glomerular filtration and permselectivity functions and promote the progressive replacement of functional glomerular cells by matrix proteins (glomerular sclerosis). Here, we focus on the pathophysiologic significance of the markedly stimulated arachidonate cyclooxygenase (CO) activity, leading to the formation of prostaglandins (PG) and thromboxane A2 (TxA2), in the mediation of progressive immune- mediated glomerular injury. It is firmly established that overall glomerular synthesis and extracellular release of these eicosanoids is enhanced markedly throughout the course of human and experimental glomerulonephritis. Equally well-documented is that inhibition of PG and or TxA2 formation or action in human and animal forms of glomerulonephritis impacts profoundly on the magnitude of changes in renal perfusion, glomerular filtration rate, and proteinuria. The influence of such inhibition on the histopathologic progression of injury is less clearly defined. Our studies will attempt an in-depth examination of the mechanisms governing the release of CO metabolites, as well as the functional and structural sequelae of enhanced CO activity throughout the course of glomerular immune injury. We will employ established models of progressive glomerular injury in the rat: anti-glomerular basement membrane antibody-induced glomerulitis, and passive Heymann nephritis. Our technical approaches will include in vivo measurement of glomerular functions (glomerular micropuncture), eicosanoid and quantitative mRNA measurements in cultured or freshly isolated glomeruli and individual glomerular cells, as well as in situ analysis of gene expression and enzyme, receptor, or matrix protein synthesis. The recent cloning of complementary DNA probes for CO and the TxA2 receptor, the availability of specific antibodies to CO, the capacity to selectively inhibit CO, thromboxane synthase, or TxA2 receptor occupancy, as well as access to highly sensitive and accurate techniques for the detection and quantitation of end-products, provide a unique opportunity to undertake this analysis with a reasonable chance for success.

Project Start
Project End
Budget Start
Budget End
Support Year
9
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Type
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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