C5a promotes development of experimental lupus nephritis which can be blocked with a specific receptor antagonist

The MRL/lpr murine SLE model has widespread complement activation and deposition of complement fragments in affected tissues. The potent anaphylatoxin C5a has the potential to play a key role in the pathogenesis of lupus nephritis. We found that renal expression of C5aR mRNA and protein was signific...

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Bibliographic Details
Published in:European journal of immunology 2005-08, Vol.35 (8), p.2496-2506
Main Authors: Bao, Lihua, Osawe, Iyabo, Puri, Tipu, Lambris, John D., Haas, Mark, Quigg, Richard J.
Format: Article
Language:English
Subjects:
Age Factors
Anaphylatoxin
Animals
Apoptosis - immunology
Autoimmunity - immunology
Blood Urea Nitrogen
Complement
Complement C5a - immunology
Inflammation - metabolism
Kidney - immunology
Kidney - metabolism
Kidney - pathology
Lupus
Lupus Nephritis - immunology
Lupus Nephritis - mortality
Lupus Nephritis - pathology
Lupus Nephritis - prevention & control
Mice
Mice, Inbred MRL lpr
Nephritis
Receptor, Anaphylatoxin C5a - antagonists & inhibitors
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Summary:The MRL/lpr murine SLE model has widespread complement activation and deposition of complement fragments in affected tissues. The potent anaphylatoxin C5a has the potential to play a key role in the pathogenesis of lupus nephritis. We found that renal expression of C5aR mRNA and protein was significantly increased in MRL/lpr mice compared to control MRL/+ mice. To examine the role of C5a signaling through C5aR, a specific small molecule antagonist (a) of C5aR was administered continuously to MRL/lpr mice from 13 to 19 wks of age. Littermate controls were given vehicle alone. The progressive impairment in renal function exhibited in the control group was prevented by C5aRa treatment. Infiltration of neutrophils and macrophages into kidneys was significantly reduced in animals treated with C5aRa compared to controls. Furthermore, renal expression of IL‐1β and MIP‐2 mRNA as well as the extent of apoptosis were significantly decreased with blockade of C5aR, indicating their dependence upon signals delivered through C5aR. Thus, pharmacological blockade of C5aR reduces disease manifestations in experimental lupus nephritis. These data support an important role for the C5a anaphylatoxin in lupus nephritis, and that blockade of C5aR represents a potentially viable treatment for human lupus nephritis.
ISSN:0014-2980
1521-4141
DOI:10.1002/eji.200526327