ROLE OF A RAT MEMBRANE INHIBITOR OF COMPLEMENT IN ANTIBASEMENT MEMBRANE ANTIBODY-INDUCED RENAL INJURY

In the kidneys of anti-glomerular basement membrane (anti-GBM) antibod y disease, binding of antibodies to tubular basement membrane (TBM) is often observed. The present work was performed to explore the mechani sms of binding of anti-GBM antibodies to TBM in vivo with special refe rence to 5I2Ag, a rat membrane inhibitor of complement which regulates complement activation at C3 convertase level. To suppress functions o f renal 5I2Ag, F(ab')2 fragment of 5I2 (a neutralizing mAb against 5I2 Ag) was perfused in the left kidney and then blood circulation was res tored. Mild proteinuria (< 10 mg/16 hr) was observed during first seve ral days. Five days later, there were tubulointerstitial injuries defi ned by tubular vimentin staining and leukocyte infiltration. Significa nt deposition of C3 was observed in the capillaries and in TBM. In rat s intravenously injected with rabbit anti-rat GBM antibodies five minu tes after kidney perfusion with 5I2, strong binding of rabbit IgG to T BM was observed at one and five days after injection. Although these r ats 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 irre levant mAb and injected with anti-GBM antibodies did not show any sign ificant binding of antibodies to TBM nor tubulointerstitial injury. Fu rthermore, rats which were made proteinuric by puromycin aminonucleosi de 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, regulate s 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.