Inhibition of glomerular mesangial cell proliferation and extracellular matrix deposition by halofuginone

• Published in: Kidney international Vol. 52; no. 6; pp. 1561 - 1569
• Main Authors: Nagler, Arnon, Katz, Avi, Aingorn, Helena, Miao, Hua-Quan, Condiotti, Reba, Genina, Olga, Pines, Mark, Vlodavsky, Israel
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.12.1997; Nature Publishing
• Subjects: Animals; Biological and medical sciences; Carbon Radioisotopes; Cell Division - drug effects; Cells, Cultured; Collagen - biosynthesis; Collagen - genetics; Collagen - metabolism; collagen type I; extracellular matrix; Extracellular Matrix - drug effects; Extracellular Matrix - metabolism; Gene Expression - drug effects; Glomerular Mesangium - cytology; Glomerular Mesangium - metabolism; glomerulosclerosis; Medical sciences; Mesangial cells; Pharmacology. Drug treatments; Piperidines; Proline - metabolism; Proline - pharmacology; Protein Synthesis Inhibitors - pharmacology; Quinazolines - pharmacology; Quinazolinones; Rats; Rats, Wistar; Sulfates - metabolism; Sulfates - pharmacology; Tritium; Urinary system; Mesangial cells; collagen type I; glomerulosclerosis; extracellular matrix; Cell proliferation; Cell culture; Proliferative glomerulonephritis; Rat; Mesangial cell; Rodentia; Biological activity; Renal glomerulus; Halofuginone; Prevention; Antiprotozoal agent; Vertebrata; Chemotherapy; Mammalia; Animal; Parasiticid; Cell cycle; Extracellular matrix; Quinolone derivatives
• ISSN: 0085-2538; 1523-1755
• DOI: 10.1038/ki.1997.486

Inhibition of glomerular mesangial cell proliferation and extracellular matrix deposition by halofuginone. 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 αl(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 Na235SO4 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.