Excessive matrix accumulation in the kidneys of MRL/lpr lupus mice is dependent on complement activation.
Complement receptor 1-related gene/protein y (Crry) in rodents is a potent membrane complement regulator that inhibits complement C3 activation by both classical and alternative pathways. Complement inhibition with Crry as the recombinant protein Crry-Ig has been demonstrated to prevent MRL/MpJ-Tnfrsf6(lpr) (MRL/lpr) mice from developing proteinuria and renal failure. Crry-Ig-treated mice also showed less glomerulosclerosis compared with control MRL/lpr mice. To clarify how complement inhibition with Crry might affect renal scarring in lupus nephritis, gene transcript profiling was performed comparing Crry-Ig-treated MRL/lpr mice to control-treated MRL/lpr mice as well as to the MRL/+ strain control. Altered gene expression was confirmed by quantitative PCR, and protein quantity with either immunoblotting or immunofluorescence microscopy. Collagens I, III, IV, and VI were overexpressed in control MRL/lpr mice, whereas complement inhibition with Crry reduced the overexpression of these extracellular matrix components toward normal. Plasminogen activator inhibitor 1, connective tissue growth factor, and TGF-beta1 were upregulated in MRL/lpr mice compared with MRL/+ mice and were normalized by Crry-Ig treatment, suggesting that the product of these genes may contribute to the progressive glomerulosclerosis in MRL/lpr mice in a complement-dependent fashion. Thus, complement inhibition with Crry has a prominent effect on matrix-related genes and proteins, which translates into improvement in functional renal disease.
D000818:Animals; D003167:Complement Activation / Q000276:immunology*; D055513:Connective Tissue Growth Factor; D005109:Extracellular Matrix / Q000276:immunology / Q000473:pathology; D005923:Glomerulosclerosis, Focal Segmental / Q000235:genetics* / Q000276:immunology*; D017874:Immediate-Early Proteins / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D007668:Kidney / Q000276:immunology* / Q000473:pathology; D051379:Mice; D019463:Mice, Inbred MRL lpr; D020411:Oligonucleotide Array Sequence Analysis; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics; D011347:Procollagen / Q000235:genetics; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1
C526318:CCN2 protein, mouse; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D017395:Plasminogen Activator Inhibitor 1; D011347:Procollagen; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D055513:Connective Tissue Growth Factor