Synergistic effects of anti-gp330 and anti-dipeptidyl peptidase type IV antibodies in the induction of glomerular damage.
Passive Heymann nephritis (PHN) in the rat is induced by the administration of heterologous antibodies to renal tubular epithelium (RTE). The nephritogenic capacity of anti-RTE resides primarily in the antibody fraction directed against a 330-kD glycoprotein (gp330). However, monospecific anti-gp330 antibodies are less nephritogenic than anti-RTE antibodies. This discrepancy led us to study a possible synergizing role for different antibody specificities present within anti-RTE. The enzyme dipeptidyl peptidase type IV (DPP IV) is, like gp330, present in RTE as well as in the glomerulus. Anti-DPP IV antibodies have been shown to induce an acute, transient proteinuria. In this study, we investigated the nephritogenic effect of separate or simultaneous administration of heterologous anti-DPP IV and anti-gp330 antibodies. Injection of anti-DPP IV antibodies resulted in a short-lived glomerular binding, and in a dose-dependent polyuria, albuminuria or proteinuria. Binding of anti-gp330 antibodies was slower, but much more stable. Albuminuria could only be observed in the heterologous phase. Combined injection did not alter antibody-binding kinetics of either antibody nor the albuminuria induced by anti-gp330. However, in the presence of anti-gp330 antibodies, a lower dose of anti-DPP IV was capable to induce transient albuminuria as compared to anti-DPP IV alone. In conclusion, anti-DPP IV and anti-gp330 antibodies bind to different sites in the glomerulus with different kinetics. The presence of anti-gp330 deposits facilitated anti-DPP-IV-induced renal injury.
van Leer
E H
EH
Department of Pathology, University of Leiden, The Netherlands.
de Roo
G M
GM
Bruijn
J A
JA
Hoedemaeker
P J
PJ
de Heer
E
E
D000419:Albuminuria / Q000139:chemically induced; D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D003167:Complement Activation; D018819:Dipeptidyl Peptidase 4; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000276:immunology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D026541:Heymann Nephritis Antigenic Complex; D007678:Kidney Glomerulus / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D008562:Membrane Glycoproteins / Q000276:immunology*; D011141:Polyuria / Q000139:chemically induced; D011507:Proteinuria / Q000139:chemically induced; D051381:Rats; D011917:Rats, Inbred Lew; D016019:Survival Analysis
D000906:Antibodies; D026541:Heymann Nephritis Antigenic Complex; D008562:Membrane Glycoproteins; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; D018819:Dipeptidyl Peptidase 4