Nagler A, Katz A, Aingorn H, Miao H Q, Condiotti R, Genina O, Pines M, Vlodavsky I
Department of Bone Marrow Transplantation, Hadassah-Hebrew University Hospital, Jerusalem, Israel.
Kidney Int. 1997 Dec;52(6):1561-9. doi: 10.1038/ki.1997.486.
Mesangial cell proliferation, increased deposition of collagen, and expansion of the mesangial extracellular matrix (ECM) are key features in the development of mesangioproliferative diseases. Halofuginone, a low molecular weight anti-coccidial quinoazolinone derivative, inhibits collagen type alpha 1(I) gene expression and synthesis. We investigated the effect of halofuginone on both normal and SV40 transformed mesangial cell proliferation, collagen synthesis, and ECM deposition. Proliferation of both cell types was almost completely inhibited in the presence of 50 ng/ml halofuginone. The cells were arrested in the late G1 phase of the cell cycle and resumed their normal growth rate following removal of the compound from the culture medium. The antiproliferative effect of halofuginone was associated with inhibition of tyrosine phosphorylation of cellular proteins. Similar results were obtained whether the mesangial cells were seeded on regular tissue culture plastic or in close contact with a naturally produced ECM resembling their local environment in vivo. Halofuginone also inhibited synthesis and deposition of ECM by mesangial cells as indicated by a substantial reduction in 14C-glycine and Na2(35)SO4 incorporation into the ECM, and by the inhibition of collagen type I synthesis and gene expression. It is proposed that by inhibiting collagen type I synthesis and matrix deposition, halofuginone exerts a potent antiproliferative effect that may be applied to inhibit mesangial cell proliferation and matrix expansion in a variety of chronic progressive glomerular diseases.
系膜细胞增殖、胶原蛋白沉积增加以及系膜细胞外基质（ECM）扩张是系膜增生性疾病发展的关键特征。常山酮是一种低分子量抗球虫喹唑啉酮衍生物，可抑制α1（I）型胶原蛋白基因的表达与合成。我们研究了常山酮对正常及SV40转化的系膜细胞增殖、胶原蛋白合成及ECM沉积的影响。在50 ng/ml常山酮存在的情况下，两种细胞类型的增殖几乎完全受到抑制。细胞停滞于细胞周期的G1晚期，从培养基中去除该化合物后恢复正常生长速率。常山酮的抗增殖作用与细胞蛋白酪氨酸磷酸化的抑制有关。无论系膜细胞接种于常规组织培养塑料上，还是与类似于其体内局部环境的天然产生的ECM紧密接触，都能得到相似的结果。常山酮还抑制系膜细胞ECM的合成与沉积，这表现为14C-甘氨酸和Na2(35)SO4掺入ECM的量大幅减少，以及I型胶原蛋白合成和基因表达受到抑制。有人提出，通过抑制I型胶原蛋白合成和基质沉积，常山酮发挥强大的抗增殖作用，可用于抑制多种慢性进行性肾小球疾病中的系膜细胞增殖和基质扩张。
