Skip Navigation



NDT Advance Access published online on November 4, 2009
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfp569
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Lee, V. W.S.
Right arrow Articles by Harris, D. C.H.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lee, V. W.S.
Right arrow Articles by Harris, D. C.H.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2009. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


The CD40–CD154 co-stimulation pathway mediates innate immune injury in adriamycin nephrosis

Vincent W.S. Lee1, Xiaohong Qin1, Yiping Wang1, Guoping Zheng1, Ya Wang1, Ying Wang1, Jon Ince1, Thian K. Tan1, Lukas K. Kairaitis1, Stephen I. Alexander2 and David C.H. Harris1

1 Centre for Transplant and Renal Research, Westmead Millennium Institute, University of Sydney at Westmead Hospital, NSW, Australia 2 Centre for Kidney Research, Children's Hospital Westmead, NSW, Australia

Correspondence and offprint requests to: Vincent Lee; E-mail: vincent_lee{at}wmi.usyd.edu.au



  Abstract

Background. Blockade of CD40–CD40 ligand (CD154) interactions protects against renal injury in adriamycin nephropathy (AN) in immunocompetent mice. To investigate whether this protection relied on adaptive or cognate immunity, we tested the effect of CD40–CD154 blockade in severe combined immunodeficient (SCID) mice.

Methods. SCID mice were divided into three groups: normal, AN + hamster IgG (ADR+IgG group) and AN + anti-CD154 antibody (MR1) (ADR+MR1 group). AN was induced by tail vein injection of 5.2 mg/kg of adriamycin (ADR). Hamster IgG (control Ab) or MR1 was administered intraperitoneally on days 5, 7, 9 and 11 after ADR injection. Histological and functional data were collected 4 weeks after ADR injection. In vitro experiments tested the effect of soluble and cell-bound CD154 co-cultured with CD40-expressing cells [macrophages, mesangial cells and renal tubular epithelial cells (RTEC)].

Results. All experimental animals developed nephropathy. Compared to the ADR+IgG group, ADR+MR1 animals had significantly less histological injury (glomerulosclerosis and tubular atrophy) and functional injury (creatinine clearance). Kidneys of ADR+MR1 animals had significantly less macrophage infiltration than those of ADR+IgG animals. Interestingly, expression of CD40 and CD41 (a platelet-specific marker) was significantly less in ADR+MR1 animals compared to ADR+IgG animals. In vitro, CD154 blockade significantly attenuated upregulation of CCL2 gene expression by RTEC stimulated by activated macrophage-conditioned medium. In contrast, platelet-induced upregulation of macrophage and mesangial cell proinflammatory cytokine gene expression were not CD154-dependent.

Conclusion. CD40–CD154 blockade has a significant innate renoprotective effect in ADR nephrosis. This is potentially due to inhibition of macrophage-derived soluble CD154.

Keywords: co-stimulation; focal sclerosing glomerulonephritis; macrophages; renal disease; tubulointerstitial injury

Received for publication: 5. 2.09
Accepted in revised form: 30. 8.09


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?




Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.