Transgenic expression of a soluble complement inhibitor protects against renal disease and promotes survival in MRL/lpr mice.
To investigate the role of complement in lupus nephritis, we used MRL/lpr mice and a transgene overexpressing a soluble complement regulator, soluble CR1-related gene/protein y (sCrry), both systemically and in kidney. Production of sCrry in sera led to significant complement inhibition in Crry-transgenic mice relative to littermate transgene negative controls. This complement inhibition with sCrry conferred a survival advantage to MRL/lpr mice. In a total of 154 animals, 42.5% transgene-negative animals had impaired renal function (blood urea nitrogen > 50 mg/dl) compared with 16.4% mice with the sCrry-producing transgene (p < 0.001). In those animals that died spontaneously, MRL/lpr mice with the sCrry-producing transgene did not die of renal failure, while those without the transgene did (blood urea nitrogen values of 46.6 +/- 9 and 122 +/- 29 mg/dl in transgene-positive and transgene-negative animals, respectively; p < 0.001). Albuminuria was reduced in those transgenic animals in which sCrry expression was maximally stimulated (urinary albumin/creatinine = 12.4 +/- 4.3 and 36.9 +/- 7.7 in transgene-positive and transgene-negative animals, respectively; p < 0.001). As expected in the setting of chronic complement inhibition, there was less C3 deposition in glomeruli of sCrry-producing transgenic mice compared with transgene-negative animals. In contrast, there was no effect on glomerular IgG deposition, levels of anti-dsDNA Ab and rheumatoid factor, or spleen weights between the two groups. Thus, long-term complement inhibition reduces renal disease in MRL/lpr mice, which translates into improved survival. MRL/lpr mice in which complement is inhibited still have spontaneous mortality, yet this is not from renal disease.
Bao
Lihua
L
Department of Medicine, Section of Nephrology, University of Chicago, Chicago, IL 60637, USA.
Haas
Mark
M
Boackle
Susan A
SA
Kraus
Damian M
DM
Cunningham
Patrick N
PN
Park
Pierce
P
Alexander
Jessy J
JJ
Anderson
Randall K
RK
Culhane
Kristin
K
Holers
V Michael
VM
Quigg
Richard J
RJ
D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology; D003176:Complement C3 / Q000378:metabolism; D003169:Complement Inactivator Proteins / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D007074:Immunoglobulin G / Q000378:metabolism; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology; D008181:Lupus Nephritis / Q000276:immunology* / Q000401:mortality* / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D008822:Mice, Transgenic; D011951:Receptors, Complement / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D017463:Receptors, Complement 3b; D016019:Survival Analysis; D019076:Transgenes / Q000276:immunology*
D003176:Complement C3; D003169:Complement Inactivator Proteins; C081470:Cr1l protein, mouse; D007074:Immunoglobulin G; D011951:Receptors, Complement; D017463:Receptors, Complement 3b