Antiglomerular basement membrane nephritis in beige mice. Deficiency of leukocytic neutral proteinases prevents the induction of albuminuria in the heterologous phase.

Abstract

Antiglomerular basement membrane (GBM) nephritis with massive albuminuria can be induced in mice by injection of heterologous antibodies against mouse GBM. The albuminuria and the glomerular lesions in this model are not mediated by complement, but are dependent on the presence of polymorphonuclear granulocytes (PMN) in the glomeruli. Neutral serine proteinases and reactive oxygen metabolites produced by activated PMN have been implicated as agents contributing to tissue damage. We examined the role of leukocytic neutral proteinases by comparing the glomerular damage and albuminuria after injection of rabbit anti-mouse GBM antibodies in normal control mice (C57BL/6J, +/+) and in beige mice (C57BL/6J,bg/bg) in which PMN are deficient of the neutral proteinases elastase and cathepsin G. The dose-dependent albuminuria that occurred in control mice after injection of 1.4-22 mg of anti-GBM antibodies was not observed in beige mice, despite a comparable influx of PMNs in the glomeruli. By electron microscopy both strains showed a similar attachment of PMN to the denuded GBM together with swelling and necrosis of endothelial cells. Elastase activity of extracts from PMN of beige mice was only 10-15% of the activity of control mice. In vitro, GBM degradation by PMN extracts of beige mice was 70% lower than that seen in control experiments. PMNs of beige and control mice showed no differences in superoxide production. In addition, administration of scavengers of reactive oxygen metabolites, such as catalase and desferrioxamine, did not prevent the albuminuria in this model. These findings support the important contribution of leukocytic neutral proteinases to the induction of albuminuria in the acute phase of anti-GBM nephritis in the mouse.

Macrophage Metalloelastase as a Major Factor for Glomerular Injury in Anti-Glomerular Basement Membrane Nephritis

“…It is possible that the dose of anti-rat rMMP-12 Ab was not enough, and MMP-12-deficient mice, which lack production of MMP-12 genetically (14), should be used to elucidate the role of MMP-12 more clearly in further study. However, given that glomerular injury is also induced by several proteinases, such as serine proteinase, elastase, and cathepsin G, or reactive oxygen metabolites from neutrophils (37)(38)(39), reactive oxygen species from macrophages (40), or also induced by direct killer activity of CD8 ϩ cells (32), our results on the effect of MMP-12 neutralization may be compatible with the fact that MMP-12 is one of the major factors, but not the absolute factor, of glomerular injury. In the present study, some of these other important mediators of glomerular injury were not detected by the gene expression profiling analysis.…”

Neutrophils: Molecules, Functions and Pathophysiological Aspects

“…Heparan sulfate constitutes the majority of anionic sites of the capillary permeability barrier and also contributes to the anticoagulant properties of GBM exposed through the glomerular endothelium fenestrae. Experiments performed in Beige mice, which have a congenital defect in neutrophil granules, have demonstrated the involvement of neutrophil proteinases in the induction of albuminuria in the heterologous phase of anti-GBM nephritis (Schrijver et al, 1989). While the importance of neutrophils in mediating glomerular injury has been well demonstrated in this experimental model, the pathogenetic role of these cells in human immune complex mediated glomerunephritis remains to be elucidated.…”

Pre-Existing Glomerular Immune Complexes Induce Polymorphonuclear Cell Recruitment Through an Fc Receptor-Dependent Respiratory Burst: Potential Role in the Perpetuation of Immune Nephritis

“…PMN are thought to damage glomeruli, including in this disease, due to a combination of reactive oxygen species and proteolytic enzymes (7). Previous studies with this model in cathepsin G/elastase deficient-mice (23,24) and an injection of a cysteine proteinase inhibitor (25) demonstrated that only early proteinuria (within day 1) was dependent on proteinase, but PMN influx and development of glomerular injury were not. Thus, we postulated that the FcR-mediated PMN respiratory burst may be a rapid and powerful effector mechanism in the early cell recruitment.…”