Anti-angiogenic compound (TNP-470) inhibits mesangial cell proliferation in vitro and in vivo.
Growth factors, especially basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), and transforming growth factor-beta (TGF-beta) are known to play key roles in the pathogenesis of mesangial proliferative glomerulonephritis. TNP-470 (AGM-1470), a potent anti-angiogenic compound, has anti-growth factor properties and inhibits the activation of cyclin-dependent kinase (cdk) 2 and phosphorylation of RB protein. We investigated whether TNP-470 could suppress growth factor induced mesangial cell proliferation in vitro and experimental model of mesangial proliferative glomerulonephritis in vivo. TNP-470 inhibited potently PDGF- and bFGF-stimulated proliferation of rat mesangial cells in vitro (IC50 = 50 pg/ml). In anti-Thy 1.1 glomerulonephritis, high dose use of TNP-470 (20 mg/kg/day) markedly suppressed mesangial cell proliferation and mesangial matrix expansion on day 6; however, mesangiolysis remained. Low dose use of TNP-470 (10 mg/kg/day) moderately inhibited mesangial cell proliferation and mesangial matrix synthesis, and induced appropriate glomerular healing on day 14 in anti-Thy 1.1 glomerulonephritis. Thus, TNP-470 potently inhibits growth factor-induced proliferation of mesangial cells in vitro, and mesangial cell proliferation and extracellular matrix expansion in anti-Thy 1.1 glomerulonephritis in vivo. These results suggest a novel therapeutic potential of TNP-470 in mesangial proliferative glomerulonephritis.
Haraguchi
M
M
First Department of Internal Medicine, Osaka City University Medical School, Japan.
Okamura
M
M
Konishi
M
M
Konishi
Y
Y
Negoro
N
N
Inoue
T
T
Kanayama
Y
Y
Yoshikawa
J
J
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003510:Cyclohexanes; D004305:Dose-Response Relationship, Drug; D005109:Extracellular Matrix / Q000378:metabolism; D005920:Glomerular Mesangium / Q000187:drug effects* / Q000473:pathology*; D005921:Glomerulonephritis / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D008297:Male; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D012717:Sesquiterpenes / Q000494:pharmacology*; D018800:Thy-1 Antigens / Q000276:immunology; D014945:Wound Healing / Q000187:drug effects
D003510:Cyclohexanes; D012717:Sesquiterpenes; D018800:Thy-1 Antigens; D000077609:O-(Chloroacetylcarbamoyl)fumagillol