Involvement of dipeptidyl peptidase IV in immune complex-mediated glomerulonephritis.
Dipeptidyl peptidase IV (DPPIV) is widely expressed in many tissues; however, its precise biological function is poorly understood. One of its possible physiologic roles is an involvement in the immune system, which plays a pivotal role in the pathogenesis of glomerulonephritis. The present study focused on the involvement of DPPIV in immune complex-mediated glomerulonephritis. Experimental nephritis was induced by anti-Thy-1.1 monoclonal antibody E30 using Wistar or F344 rats. The application of a new monoclonal antibody against DPPIV, F16, completely suppressed E30-induced proteinuria and mesangial proliferation in Wistar rats, whereas these preventive effects of F16 were not observed in F344 rats, which spontaneously lack DPPIV protein. Treatment with F16 inhibited glomerular deposition of complement C3 and complement C4 after the binding of E30 to the mesangial cell surface. Because the preventive effect of F16 was attributable to suppression of the complement cascade, we examined its influences on complement-dependent mesangial cell lysis in vitro. We discovered that the complement cascade was markedly inactivated in F16-treated Wistar rat serum but not in F16-treated F344 rats. These results indicate that DPPIV may play a somewhat crucial role in regulating the complement cascade and that inhibition of DPPIV may serve as a new target for preventing complement-dependent tissue injury.
Shinosaki
Toshihiro
T
Shionogi Discovery Research Laboratories, Shionogi and Company, Ltd., Toyonaka-City, Osaka, Japan. toshihiro.shinosaki@shionogi.co.jp
Kobayashi
Tatsuo
T
Kimura
Kazuhiro
K
Kurihara
Hidetake
H
D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D000936:Antigen-Antibody Complex / Q000276:immunology; D001665:Binding Sites / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D003176:Complement C3 / Q000378:metabolism; D003181:Complement C4 / Q000378:metabolism; D015938:Complement Membrane Attack Complex / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D018819:Dipeptidyl Peptidase 4 / Q000096:biosynthesis* / Q000276:immunology; D005920:Glomerular Mesangium / Q000166:cytology / Q000276:immunology; D005921:Glomerulonephritis / Q000201:enzymology* / Q000276:immunology; D007105:Immune Complex Diseases / Q000201:enzymology* / Q000276:immunology / Q000517:prevention & control; D007518:Isoantibodies / Q000008:administration & dosage; D008297:Male; D011507:Proteinuria / Q000517:prevention & control; D051381:Rats; D011916:Rats, Inbred F344; D017208:Rats, Wistar; D013045:Species Specificity
D019138:Antibodies, Blocking; D000936:Antigen-Antibody Complex; D003176:Complement C3; D003181:Complement C4; D015938:Complement Membrane Attack Complex; D007518:Isoantibodies; C035678:anti-Thy antibody; D018819:Dipeptidyl Peptidase 4