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NDT Advance Access published online on September 27, 2006
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfl555
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© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received April 14, 2006
Accepted August 18, 2006

Original Article

Up-regulation of adhesion molecule expression in glomerular endothelial cells by anti-myeloperoxidase antibody

Tomokazu Nagao 1, Mimiko Matsumura 2, Ayako Mabuchi 3, Akiko Ishida-Okawara 1, Osamu Koshio 4, Toshinori Nakayama 5, Haruyuki Minamitani 6, and Kazuo Suzuki 1 *

1 Department of Bioactive Molecules, National Institute of Infectious Diseases, Tokyo, Japan
2 Department of Bioactive Molecules, National Institute of Infectious Diseases, Tokyo, Japan; Graduate School of Science and Technology, Keio University, Yokohama, Japan
3 Department of Physiology, University of Otago, Dunedin, New Zealand
4 Department of Medicine, Teikyo University, Tokyo, Japan
5 Graduate School of Medicine, Chiba University, Chiba, Japan
6 Graduate School of Science and Technology, Keio University, Yokohama, Japan

* To whom correspondence should be addressed.
Kazuo Suzuki, E-mail: ksuzuki{at}nih.go.jp



  Abstract

Background. Anti-neutrophil cytoplasmic antibody directed against myeloperoxidase (MPO-ANCA) has been implicated in pauci-immune crescentic glomerulonephritis. It stimulates primed neutrophils to adhere to glomerular endothelial cells (GECs), thereby releasing reactive oxygen and other toxic substances and ultimately damaging the GECs. Though, a pathogenic role for MPO-ANCA is not fully understood, we hypothesized that MPO-ANCA modulates GEC functions by the increases in expression of adhesion molecules.

Methods. A polyclonal rabbit anti-recombinant mouse MPO antibody (anti-rmMPO IgG) was evaluated in mouse GEC (mGEC) for its effect on adhesion molecule expression. The primary culture of mGEC was incubated with anti-rmMPO IgG or isotype control and the expression of intercellular adhesion molecules-1 (ICAM-1) was evaluated by real-time reverse transcription-polymerase chain reaction (RT-PCR) analysis and ICAM-1 cell ELISA.

Results. The real-time RT-PCR analysis showed that a treatment with 100 µg/ml anti-rmMPO IgG increased the expression of mRNAs for ICAM-1, vascular cell adhesion molecule-1 and E-selectin by approximately, 12.5, 7.5 and 10.5-fold, respectively. ICAM-1 cell ELISA also substantiated increased expression of ICAM-1. This enhancement of ICAM-1 expression was mediated by the antigen specificity of anti-rmMPO IgG. In addition, there were several proteins in mGEC specifically immunoprecipitated with anti-rmMPO IgG.

Conclusions. These results showed that anti-MPO antibody activates not only neutrophils, but also GEC, indicating that anti-rmMPO IgG-induced direct activation of GEC contributes to neutrophil adhesion to GEC, thereby increasing glomerular neutrophil infiltration in initiation and progression of pauci-immune glomerulonephritis.

Keywords: adhesion molecules; crescentic glomerulonephritis; glomerular endothelial cells; MPO-ANCA.
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