Role of a rat membrane inhibitor of complement in anti-basement membrane antibody-induced renal injury.
In the kidneys of anti-glomerular basement membrane (anti-GBM) antibody disease, binding of antibodies to tubular basement membrane (TBM) is often observed. The present work was performed to explore the mechanisms of binding of anti-GBM antibodies to TBM in vivo with special reference to 5I2Ag, a rat membrane inhibitor of complement which regulates complement activation at C3 convertase level. To suppress functions of renal 5I2Ag, F(ab')2 fragment of 5I2 (a neutralizing mAb against 5I2Ag) was perfused in the left kidney and then blood circulation was restored. Mild proteinuria ( < 10 mg/16 hr) was observed during first several days. Five days later, there were tubulointerstitial injuries defined by tubular vimentin staining and leukocyte infiltration. Significant deposition of C3 was observed in the capillaries and in TBM. In rats intravenously injected with rabbit anti-rat GBM antibodies five minutes after kidney perfusion with 5I2, strong binding of rabbit IgG to TBM was observed at one and five days after injection. Although these rats showed mild proteinuria comparable to those perfused with 5I2 and those injected with normal rabbit serum, tubulointerstitial injury was significantly enhanced at Day 5. In contrast, rats perfused with irrelevant mAb and injected with anti-GBM antibodies did not show any significant binding of antibodies to TBM nor tubulointerstitial injury. Furthermore, rats which were made proteinuric by puromycin aminonucleoside and injected with anti-GBM antibodies did not show any significant binding of rabbit IgG to TBM. These results indicate that 5I2Ag, a rat membrane inhibitor of complement at the C3 convertase level, regulates vascular permeability in the living kidney, and that dysfunction or decreased expression of this molecule leads to increased accessibility of anti-GBM antibodies to TBM.
Hatanaka
Y
Y
Third Department of Internal Medicine, Nagoya University School of Medicine, Japan.
Yuzawa
Y
Y
Nishikawa
K
K
Fukatsu
A
A
Okada
N
N
Okada
H
H
Mizuno
M
M
Matsuo
S
S
D000419:Albuminuria / Q000652:urine; D000704:Analysis of Variance; D000818:Animals; D000911:Antibodies, Monoclonal; D001485:Basement Membrane / Q000378:metabolism*; D003176:Complement C3 / Q000378:metabolism*; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D007074:Immunoglobulin G / Q000378:metabolism*; D009395:Nephritis, Interstitial / Q000378:metabolism* / Q000473:pathology; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar
D000911:Antibodies, Monoclonal; D003176:Complement C3; D007074:Immunoglobulin G