Nephrol Dial Transplant Vol. 19 No. 12 © ERA-EDTA 2004; all rights reserved
Original Article
Important role for macrophages in induction of crescentic anti-GBM glomerulonephritis in WKY rats
1 Department of Structural Pathology, Institute of Nephrology and 4 Second Department of Pathology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, 2 Department of Pediatrics, Fukushima Medical University School of Medicine, Fukushima, 3 Department of Pediatrics, Niigata National Hospital, Kashiwazaki and 5 Department of Cell Pathology, Kumamoto University Faculty of Medical and Pharmaceutical Sciences, Kumamoto, Japan
Correspondence and offprint requests to: Hidehiko Fujinaka, MD, PhD, Department of Structural Pathology, Institute of Nephrology, Niigata University Graduate School of Medical and Dental Sciences, 757 Asahimachi-dori-1-bancho, Niigata 951-8510, Japan. E-mail: dexter{at}med.niigata-u.ac.jp
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/M
), 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/M 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/M 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/M in induction of GN were examined in animals by depleting Mo/M 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/M 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/M depletion.
Conclusion. These results indicate that Mo/M play an important role in the induction of crescentic anti-GBM GN and glomerular injury.
Keywords: anti-GBM glomerulonephritis; CD8; macrophage; monocyte; receptor; scavenger
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