Haraguchi M, Okamura M, Konishi M, Konishi Y, Negoro N, Inoue T, Kanayama Y, Yoshikawa J
First Department of Internal Medicine, Osaka City University Medical School, Japan.
Kidney Int. 1997 Jun;51(6):1838-46. doi: 10.1038/ki.1997.251.
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.
已知生长因子，尤其是碱性成纤维细胞生长因子（bFGF）、血小板衍生生长因子（PDGF）和转化生长因子-β（TGF-β）在系膜增生性肾小球肾炎的发病机制中起关键作用。TNP-470（AGM-1470）是一种有效的抗血管生成化合物，具有抗生长因子特性，可抑制细胞周期蛋白依赖性激酶（cdk）2的激活和RB蛋白的磷酸化。我们研究了TNP-470是否能在体外抑制生长因子诱导的系膜细胞增殖以及在体内系膜增生性肾小球肾炎实验模型中发挥作用。TNP-470在体外能有效抑制PDGF和bFGF刺激的大鼠系膜细胞增殖（IC50 = 50 pg/ml）。在抗Thy 1.1肾小球肾炎中，高剂量使用TNP-470（20 mg/kg/天）在第6天可显著抑制系膜细胞增殖和系膜基质扩张；然而，系膜溶解现象仍然存在。低剂量使用TNP-470（10 mg/kg/天）在抗Thy 1.1肾小球肾炎中第14天可适度抑制系膜细胞增殖和系膜基质合成，并诱导适当的肾小球愈合。因此，TNP-470在体外能有效抑制生长因子诱导的系膜细胞增殖，在体内抗Thy 1.1肾小球肾炎中能抑制系膜细胞增殖和细胞外基质扩张。这些结果提示TNP-470在系膜增生性肾小球肾炎中具有新的治疗潜力。
