TRAPIDIL INHIBITS HUMAN MESANGIAL CELL-PROLIFERATION - EFFECT ON PDGFBETA-RECEPTOR BINDING AND EXPRESSION

Mesangial cell (MC) proliferation, a histopathologic feature common to many human glomerular diseases, is regulated by several growth factor s through their binding to specific cell surface receptors. Platelet-d erived growth factor (PDGF) is a peptide exerting a potent mitogenic a ctivity on MC. Recently, an increased expression of both PDGF protein and its receptor has been localized in the mesangial areas of several experimental as well as human proliferative glomerulonephritides (GN). Thus, it may be postulated that the inhibition of PDGF action could p revent MC proliferation during mesangial proliferative GN. Trapidil, a n antiplatelet drug, has been shown to inhibit the growth of several c ell types both in vitro and in vivo. The present study was aimed at ev aluating the effect of Trapidil on human MC in vitro. The addition of 100 to 400 mu g/ml Trapidil significantly reduced cell proliferation i nduced by different growth factors (FCS, PDGF-BB, bFGF, EGF), the high est inhibitory effect being on PDGF-BB stimulated MC growth. The effec t of the drug was dose-dependent and seemingly specific: aspirin was d evoid of any anti-proliferative action, while dypiridamole proved to b e toxic. Receptor binding experiments showed that Trapidil competitive ly inhibited I-125-PDGF-BB binding to its cell surface receptors, with out inducing receptor internalization, at least after short-term (2 hr ) incubation. In contrast, long-term (48 hr) exposure to 400 mu g/ml T rapidil caused a sharp increase of PDGF-BB binding. Similar effects on cell proliferation and I-125-PDGF-BB binding were observed when NIH-3 T3 fibroblasts were exposed to the test substance. Finally, we evaluat ed the influence of Trapidil on PDGF beta-receptor gene expression and found that 24 hour exposure to 400 mu g/ml Trapidil moderately decrea sed steady-state mRNA levels, whereas 48 hours of incubation increased PDGF beta-receptor transcript levels by approximately threefold. We c onclude that Trapidil is able to strongly inhibit human MC proliferati on, a process in which inhibition of PDGF-BB binding to its receptors and modulation of PDGF beta-receptor gene expression might be involved .