Excessive Matrix Accumulation in the Kidneys of MRL/lprLupus Mice Is Dependent on Complement Activation

Abstract

ABSTRACT. 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-Tnfrsf6lpr(MRL/lpr) mice from developing proteinuria and renal failure. Crry-Ig–treated mice also showed less glomerulosclerosis compared with control MRL/lprmice. To clarify how complement inhibition with Crry might affect renal scarring in lupus nephritis, gene transcript profiling was performed comparing Crry-Ig–treated MRL/lprmice to control-treated MRL/lprmice 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/lprmice, 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-β1 were upregulated in MRL/lprmice 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/lprmice 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. E-mail: rquigg@medicine.uchicago.edu