C3a receptor deficiency accelerates the onset of renal injury in the MRL/lpr mouse.
The development and progression of systemic lupus erythematosus (SLE) is strongly associated with complement activation and deposition. The anaphylatoxin C3a is a product of complement activation with immunomodulatory properties, and the receptor for C3a (C3aR) is not only expressed by granulocytes and antigen presenting cell populations, but it is also strongly up-regulated in lupus prone mice with active nephritis. In order to characterize the role of the C3aR in inflammatory nephritis, we bred C3aR knock out mice onto the MRL/lpr genetic background (C3aR KO MRL). Compared to control MRL/lpr mice, C3aR KO MRL mice had elevated auto-antibody titers and an earlier onset of renal injury. At 8 weeks, renal expression of a wide range of chemokines and chemokine receptors was increased in C3aR KO MRL kidneys compared to controls. Only the expression of MCP-1 was significantly decreased in the C3aR KO MRL mice. The increased chemokine and chemokine receptor expression seen in the C3aR KO MRL mice was associated with a more rapid rise in serum creatinine and the acceleration of renal fibrosis. However, loss of the C3aR had little impact on long-term kidney injury and did not alter survival. These findings suggest that activation of the C3aR plays a protective, not pathologic, role in the early phase of inflammatory nephritis in the MRL/lpr model of SLE.
Wenderfer
Scott E
SE
The Center for Immunology and Autoimmune Diseases, Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, University of Texas Health Science Center-Houston, Houston, TX 77030, USA.
Wang
Hongyu
H
Ke
Baozhen
B
Wetsel
Rick A
RA
Braun
Michael C
MC
D000818:Animals; D018450:Disease Progression; D020022:Genetic Predisposition to Disease; D008181:Lupus Nephritis / Q000150:complications / Q000235:genetics* / Q000401:mortality; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D011951:Receptors, Complement / Q000235:genetics* / Q000502:physiology; D016019:Survival Analysis; D013997:Time Factors
D011951:Receptors, Complement; C085567:complement C3a receptor