Glomerulonephritides (GN) are associated with leukocyte migration and resident glomerular cell proliferation. Adhesion molecules are implicated in these processes. The objective of this proposal is to assess the effect of deficiencies in select leukocyte adhesion receptors and the extracellular matrix molecule thrombospondin on renal injury in murine models of glomerulonephritis developed by our group: acute, passive anti- glomerular basement membrane nephritis, complement dependent acute nephrotoxic serum nephritis and accelerated nephrotoxic serum nephritis associated with cellular proliferation, mesangial sclerosis and massive proteinuria. To accomplish these studies we have in a collaborative effort, or have generated using gene targeting technology, mice deficient in leukocyte adhesion receptors, selectins (P-, E-, P- and E-, and L- selectin), ICAM-1, ICAM-1 and P-selectin, Mac-1, and mice deficient in thrombospondin 1. The selectins support leukocyte rolling and loose adhesion on the venular endothelium which is a prerequisite to firm adhesion promoted by members of the leukocyte beta2 integrins (e.g., Mac- 1) and IgG superfamily (e.g., ICAM-1). However, the relevance of the paradigm of leukocyte rolling, firm adhesion and extravasation examined in a limited number of tissues, to the specialized microvasculature of the glomeruli remains controversial. Thrombospondin, an extracellular matrix molecule is a potent stimulator of mesangial cell proliferation in vitro although the in vivo implications of this have not been extensively studied. Our working hypothesis is that leukocyte adhesion molecules and thrombospondin play a pivotal role in glomerular hypercellularity by mediating leukocyte infiltration and resident glomerular cell proliferation respectively. In support of our hypothesis, we have found that acute, passive anti-glomerular basement membrane nephritis in mice deficient in P-selectin, an endothelial and platelet selectin, leads to increased glomerular neutrophil influx and markedly higher urine proteinuria compared to wild-type mice. Our studies further demonstrated a role for P-selectin mediated platelet-neutrophil interaction in GN in the transcellular biosynthesis of lipoxin A4, previously proposed as a potent """"""""stop-signal"""""""" for neutrophil influx (preliminary results). Knock- outs remain a powerful adjunct to understanding the role of adhesion molecules in inflammatory disease and will contribute to a comprehensive understanding of the role of leukocyte adhesion molecules and thrombospondin in glomerulonephritis.
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