INHIBITION OF GLOMERULAR MESANGIAL CELL-PROLIFERATION AND EXTRACELLULAR-MATRIX DEPOSITION BY HALOFUGINONE

Mesangial cell proliferation, increased deposition of collagen, and ex pansion of the mesangial extracellular matrix (ECM) are key features i n the development of mesangioproliferative diseases. Halofuginone, a l ow molecular weight anti-coccidial quinoazolinone derivative, inhibits collagen type alpha 1(I) gene expression and synthesis. We investigat ed the effect of halofuginone on both normal and SV40 transformed mesa ngial cell proliferation, collagen synthesis, and ECM deposition. Prol iferation of both cell types was almost completely inhibited in the pr esence of 50 ng/ml halofuginone. The cells were arrested in the late G (1) phase of the cell cycle and resumed their normal growth rate follo wing removal of the compound from the culture medium. The antiprolifer ative effect of halofuginone was associated with inhibition of tyrosin e phosphorylation of cellular proteins. Similar results were obtained whether the mesangial cells were seeded on regular tissue culture plas tic 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 red uction in C-14-glycine and (Na2SO4)-S-35 incorporation into the ECM, a nd by the inhibition of collagen type I synthesis and gene expression. It is proposed that by inhibiting collagen type I synthesis and matri x deposition, halofuginone exerts a potent antiproliferative effect th at may be applied to inhibit mesangial cell proliferation and matrix e xpansion in a variety of chronic progressive glomerular diseases.