Important role for macrophages in induction of crescentic anti-GBM glomerulonephritis in WKY rats

Abstract

Background. A crucial role for CD8+ cells in induction of crescentic anti-glomerular basement membrane (GBM) glomerulonephritis (GN) in WKY rats was demonstrated in studies showing that depletion of CD8+ cells completely suppressed glomerular accumulation of monocytes/macrophages (Mo/Mφ), crescent formation and proteinuria. Because these studies did not definitively identify CD8+ cells as the cause of tissue injury, we examined the roles of Mo/Mφ in the development of anti-GBM GN. Methods. We examined correlations between the amount of urinary protein and the numbers of glomerular CD8+ cells or Mo/Mφ in rats after administrating different doses of anti-GBM antibody (5.0, 7.5, 10.0 and 25.0 μl/100 g body weight). The roles of Mo/Mφ in induction of GN were examined in animals by depleting Mo/Mφ in the glomerulus. To do this, rats were injected intravenously with liposome-encapsulated dichloromethylene diphosphonate (liposome-MDP) from day 3 to day 7 after anti-GBM antibody injection and they were then sacrificed at day 8. Results. Liposome-MDP treatment significantly reduced the number of ED-1+ Mo/Mφ accumulated in glomeruli from 32.1 ± 1.2 to 1.4 ± 0.3/glomerular cross-section (mean ± SD, P < 0.01), and the amount of urinary protein from 103.8 ± 19.8 to 31.8 ± 15.9 mg/day (P<0.01), as well as the incidence of crescentic glomeruli from 91.3 ± 2.7 to 23.3 ± 7.6% (P<0.01) at day 8. This treatment also reduced the number of CD8+ cells accumulating in the glomeruli from 5.4 ± 0.7 to 0.5 ± 0.1/glomerular cross-section (P<0.01). Upregulation of glomerular intercellular adhesion molecule 1 (ICAM-1) and monocyte chemoattractant protein 1 (MCP-1) mRNA expression was suppressed by Mo/Mφ depletion. Conclusion. These results indicate that Mo/Mφ play an important role in the induction of crescentic anti-GBM GN and glomerular injury. © ERA-EDTA 2004; all rights reserved.