PDGF signal transduction inhibition ameliorates experimental mesangial proliferative glomerulonephritis.
BACKGROUND
Platelet-derived growth factor (PDGF) has been consistently implicated in the cell proliferation and extracellular matrix accumulation, which characterize progressive glomerular disease. In the present study, the effects of a potent and selective inhibitor of PDGF receptor tyrosine kinase, STI 571, were examined in vitro and in vivo.


METHODS
Cultured mesangial cells were incubated with PDGF (50 ng/mL) and fibroblast growth factor-2 (FGF-2; 50 ng/mL) and treated with STI 571 (0.13 to 2.0 micromol/L). Experimental mesangial proliferative glomerulonephritis was induced in male Wistar rats with monoclonal OX-7, anti-rat Thy-1.1 antibody with rats randomized to receive either STI 571 (50 mg/kg intraperitoneally daily) or vehicle. Animals were examined six days later.


RESULTS
In vitro, both PDGF and FGF-2 induced a threefold increase in mesangial cell 3H-thymidine incorporation. STI 571 reduced PDGF but not FGF-2-stimulated mesangial cell proliferation in a dose-dependent manner, with complete abolition at 0.4 micromol/L. In animals with Thy-1.1 glomerulonephritis, PDGF receptor tyrosine kinase blockade was associated with significant reductions in mesangial cell proliferation (P < 0.001), the number of activated (alpha-smooth muscle positive) mesangial cells, and glomerular type IV collagen deposition (P < 0.001).


CONCLUSIONS
The amelioration of the pathological findings of experimental mesangial proliferative glomerulonephritis by blockade of PDGF receptor activity suggests the potential clinical utility of this approach as a therapeutic strategy in glomerular disease.
Department of Medicine, University of Melbourne, St. Vincent's, Victoria, Australia. gilbert@medstv.unimelb.edu.au
R E
RE
Gilbert
D J
DJ
Kelly
T
T
McKay
S
S
Chadban
P A
PA
Hill
M E
ME
Cooper
R C
RC
Atkins
D J
DJ
Nikolic-Paterson
D000818:Animals; D001549:Benzamides; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D003094:Collagen / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D005920:Glomerular Mesangium / Q000187:drug effects* / Q000473:pathology; D015432:Glomerulonephritis, Membranoproliferative / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D000068877:Imatinib Mesylate; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology; D008297:Male; D010879:Piperazines / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000502:physiology*; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects*; D018800:Thy-1 Antigens / Q000276:immunology
D001549:Benzamides; D004791:Enzyme Inhibitors; D010879:Piperazines; D010982:Platelet-Derived Growth Factor; D011743:Pyrimidines; D018800:Thy-1 Antigens; D016222:Fibroblast Growth Factor 2; D000068877:Imatinib Mesylate; D003094:Collagen; C099852:PDGF receptor tyrosine kinase; D017479:Receptors, Platelet-Derived Growth Factor