Endogenous fibroblast growth factor-2 mediates cytotoxicity in experimental mesangioproliferative glomerulonephritis.
Fibroblast growth factor-2 (FGF-2) is released from mesangial cells in experimental mesangioproliferative glomerulonephritis induced with anti-Thy 1.1 antibody. To investigate the functional role of released FGF-2, rats received either neutralizing anti-FGF-2 IgG or a functional peptide antagonist of FGF-2 (FGF119-126) before or shortly after induction of anti-Thy 1.1 nephritis. In additional experiments, rats were treated with bolus injections of FGF-2 from 2 to 6 h after disease induction. The data showed that anti-FGF-2 therapy led to significant reductions of early mesangial cell injury (mesangiolysis, microaneurysm formation) and the subsequent mesangioproliferative changes (glomerular de novo expression of alpha-smooth muscle actin, mesangial cell proliferation, matrix accumulation, and platelet influx). Conversely, injections of FGF-2 augmented both mesangial injury and the subsequent mesangioproliferative changes. Studies on the mechanisms underlying the amplification of mesangial cell injury by FGF-2 showed that anti-FGF-2 therapy reduced cell death at 2 and 8 h after disease induction by 58 and 54%, respectively. This was associated with significant reductions in the number of glomerular H2O2- and OH -producing cells, as well as reduced glomerular production of nitric oxide. These data suggest that release of constitutively expressed FGF-2 after immune-mediated cell injury contributes to glomerular cell damage and thus identify FGF-2 as a novel mediator of cytotoxicity.
Floege
J
J
Division of Nephrology, Medizinische Hochschule, Hannover, Germany.
Burg
M
M
Hugo
C
C
Gordon
K L
KL
Van Goor
H
H
Reidy
M
M
Couser
W G
WG
Koch
K M
KM
Johnson
R J
RJ
D000818:Animals; D000906:Antibodies / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000502:physiology*; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*; D015432:Glomerulonephritis, Membranoproliferative / Q000276:immunology* / Q000473:pathology; D006041:Goats; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D007672:Kidney Cortex / Q000473:pathology; D007678:Kidney Glomerulus / Q000473:pathology; D008297:Male; D010446:Peptide Fragments / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins
D000906:Antibodies; D007074:Immunoglobulin G; D010446:Peptide Fragments; D011994:Recombinant Proteins; D016222:Fibroblast Growth Factor 2