ANTI-ANGIOGENIC COMPOUND (TNP-470) INHIBITS MESANGIAL CELL-PROLIFERATION IN-VITRO AND IN-VIVO

Growth factors, especially basic fibroblast growth factor (bFGF), plat elet-derived growth factor (PDGF), and transforming growth factor-beta (TGF-beta) are known to play key roles in the pathogenesis of mesangi al proliferative glomerulonephritis. TNP-470 (AGM-1470), a potent anti -angiogenic compound, has anti-growth factor properties and inhibits t he activation of cyclin-dependent kinase (cdk) 2 and phosphorylation o f RB protein. We investigated whether TNP-470 could suppress growth fa ctor induced mesangial cell proliferation in vitro and experimental mo del of mesangial proliferative glomerulonephritis in vivo. TNP-470 inh ibited potently PDGF- and bFGF-stimulated proliferation of rat mesangi al cells in vitro (IC50 = 50 pg/ml). In anti-Thy 1.1 glomerulonephriti s, high dose use of TNP-470 (20 mg/kg/day) markedly suppressed mesangi al cell proliferation and mesangial matrix expansion on day 6; however , mesangiolysis remained. Low dose use of TNP-470 (10 mg/kg/day) moder ately inhibited mesangial cell proliferation and mesangial matrix synt hesis, and induced appropriate glomerular healing on day 14 in anti-Th y 1.1 glomerulonephritis. Thus, TNP-470 potently inhibits growth facto r-induced proliferation of mesangial cells in vitro, and mesangial cel l proliferation and extracellular matrix expansion in anti-Thy 1.1 glo merulonephritis in vivo. These results suggest a novel therapeutic pot ential of TNP-470 in mesangial proliferative glomerulonephritis.