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 mu mol/L). Experimental mesangial proliferative gromerulonephritis 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 H-3-thymidine incorporation. STI 571 reduced PD GF but not FGF-2-stimulated mesangial cell proliferation in a dose-dependent manner; with complete abolition at 0.4 mu mol/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). Conclusion. 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 gromerular disease.