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Inhibition of glomerular mesangial cell proliferation and extracellular matrix deposition by halofuginone
1Department of Bone Marrow Transplantation, Hadassah-Hebrew University Hospital, Jerusalem, Israel.
Abstract:
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.
Insights
Halofuginone effectively inhibits mesangial cell proliferation and extracellular matrix deposition by blocking collagen synthesis. This compound shows potential for treating chronic progressive glomerular diseases by reducing mesangial cell overgrowth.
Area of Science:
- Nephrology
- Cell Biology
- Pharmacology
Background:
- Mesangial cell proliferation and extracellular matrix (ECM) expansion characterize mesangioproliferative diseases.
- Collagen synthesis and deposition are key contributors to these pathological processes.
Purpose of the Study:
- To investigate the effects of halofuginone on mesangial cell proliferation, collagen synthesis, and ECM deposition.
- To assess halofuginone's impact on both normal and SV40-transformed mesangial cells.
Main Methods:
- Mesangial cells (normal and SV40-transformed) were treated with halofuginone.
- Cell proliferation was monitored, and cell cycle progression was analyzed.
- Collagen synthesis and ECM deposition were quantified using radiolabeled precursors (14C-glycine, Na2(35)SO4).
- Collagen type I gene expression and protein synthesis were assessed.
Main Results:
- Halofuginone (50 ng/ml) almost completely inhibited proliferation of both normal and transformed mesangial cells.
- Cell cycle arrest occurred in the late G1 phase, with normal growth resuming after halofuginone removal.
- Halofuginone significantly reduced ECM synthesis and deposition, including collagen type I.
- The antiproliferative effect correlated with the inhibition of tyrosine phosphorylation of cellular proteins.
Conclusions:
- Halofuginone exhibits potent antiproliferative effects on mesangial cells.
- Inhibition of collagen type I synthesis and ECM deposition by halofuginone is a key mechanism underlying its antiproliferative action.
- Halofuginone holds therapeutic potential for inhibiting mesangial cell proliferation and matrix expansion in chronic progressive glomerular diseases.