Mesangial cell (MC) proliferation, a histopathologic feature common to many human glomerular diseases, is regulated by several growth factors through their binding to specific cell surface receptors. Platelet-derived growth factor (PDGF) is a peptide exerting a potent mitogenic activity 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 prevent MC proliferation during mesangial proliferative GN. Trapidil, an antiplatelet drug, has been shown to inhibit the growth of several cell types both in vitro and in vivo. The present study was aimed at evaluating the effect of Trapidil on human MC in vitro. The addition of 100 to 400 mu g/ml Trapidil significantly reduced cell proliferation induced by different growth factors (FCS, PDGF-BB, bFGF, EGF), the highest inhibitory effect being on PDGF-BB stimulated MC growth. The effect of the drug was dose-dependent and seemingly specific: aspirin was devoid of any anti-proliferative action, while dypiridamole proved to be toxic. Receptor binding experiments showed that Trapidil competitively inhibited I-125-PDGF-BB binding to its cell surface receptors, without inducing receptor internalization, at least after short-term (2 hr) incubation. In contrast, long-term (48 hr) exposure to 400 mu g/ml Trapidil caused a sharp increase of PDGF-BB binding. Similar effects on cell proliferation and I-125-PDGF-BB binding were observed when NIH-3T3 fibroblasts were exposed to the test substance. Finally, we evaluated the influence of Trapidil on PDGF beta-receptor gene expression and found that 24 hour exposure to 400 mu g/ml Trapidil moderately decreased steady-state mRNA levels, whereas 48 hours of incubation increased PDGF beta-receptor transcript levels by approximately threefold. We conclude that Trapidil is able to strongly inhibit human MC proliferation, a process in which inhibition of PDGF-BB binding to its receptors and modulation of PDGF beta-receptor gene expression might be involved.

Trapidil inhibits human mesangial cells proliferation: effect on PDGF-β receptor binding and expression

GESUALDO, LORETO;RANIERI, ELENA;
1994

Abstract

Mesangial cell (MC) proliferation, a histopathologic feature common to many human glomerular diseases, is regulated by several growth factors through their binding to specific cell surface receptors. Platelet-derived growth factor (PDGF) is a peptide exerting a potent mitogenic activity 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 prevent MC proliferation during mesangial proliferative GN. Trapidil, an antiplatelet drug, has been shown to inhibit the growth of several cell types both in vitro and in vivo. The present study was aimed at evaluating the effect of Trapidil on human MC in vitro. The addition of 100 to 400 mu g/ml Trapidil significantly reduced cell proliferation induced by different growth factors (FCS, PDGF-BB, bFGF, EGF), the highest inhibitory effect being on PDGF-BB stimulated MC growth. The effect of the drug was dose-dependent and seemingly specific: aspirin was devoid of any anti-proliferative action, while dypiridamole proved to be toxic. Receptor binding experiments showed that Trapidil competitively inhibited I-125-PDGF-BB binding to its cell surface receptors, without inducing receptor internalization, at least after short-term (2 hr) incubation. In contrast, long-term (48 hr) exposure to 400 mu g/ml Trapidil caused a sharp increase of PDGF-BB binding. Similar effects on cell proliferation and I-125-PDGF-BB binding were observed when NIH-3T3 fibroblasts were exposed to the test substance. Finally, we evaluated the influence of Trapidil on PDGF beta-receptor gene expression and found that 24 hour exposure to 400 mu g/ml Trapidil moderately decreased steady-state mRNA levels, whereas 48 hours of incubation increased PDGF beta-receptor transcript levels by approximately threefold. We conclude that Trapidil is able to strongly inhibit human MC proliferation, a process in which inhibition of PDGF-BB binding to its receptors and modulation of PDGF beta-receptor gene expression might be involved.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11369/15055
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