Important role for macrophages in induction of crescentic anti-GBM glomerulonephritis in WKY rats.
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/Mphi), 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/Mphi 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/Mphi in rats after administrating different doses of anti-GBM antibody (5.0, 7.5, 10.0 and 25.0 microl/100 g body weight). The roles of Mo/Mphi in induction of GN were examined in animals by depleting Mo/Mphi 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/Mphi 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/Mphi depletion.


CONCLUSIONS
These results indicate that Mo/Mphi play an important role in the induction of crescentic anti-GBM GN and glomerular injury.
Isome
Masato
M
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.
Fujinaka
Hidehiko
H
Adhikary
Laxman P
LP
Kovalenko
Pavel
P
El-Shemi
Adel G Ahmed
AG
Yoshida
Yutaka
Y
Yaoita
Eishin
E
Takeishi
Toshiyuki
T
Takeya
Motohiro
M
Naito
Makoto
M
Suzuki
Hitoshi
H
Yamamoto
Tadashi
T
D000818:Animals; D000906:Antibodies; D001485:Basement Membrane / Q000276:immunology / Q000473:pathology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D005921:Glomerulonephritis / Q000276:immunology / Q000473:pathology*; D007150:Immunohistochemistry; D007678:Kidney Glomerulus / Q000276:immunology / Q000473:pathology*; D008264:Macrophages; D011507:Proteinuria / Q000209:etiology / Q000473:pathology; D051381:Rats; D011921:Rats, Inbred WKY
D000906:Antibodies