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Effect of heparin on mesangial cell growth and gene expression of matrix proteins
Background:
Mesangial cell (MC) proliferation and matrix expansion are characteristics of many glomerulopathies. Heparin has been shown to inhibit MC proliferation in vitro and mitigate cell proliferation, matrix expansion, proteinuria, renal insufficiency, and hypertension in experimental glomerulonephritis and subtotal renal ablation. We examined the effect of standard heparin on MC proliferation and matrix protein expression in vitro which necessarily excludes the confounding influences of haemodynamic, inflammatory, haemostatic, and various other processes that are present in vivo.
Methods:
Gene expression and release of fibronectin (FN), collagen IV and laminin by cultured rat MC were tested in the presence and absence of heparin. In addition the effect of transforming growth factor-beta1 (TGF-beta1) on the gene expression of those matrix proteins was assessed.
Results:
Within a 3-1000 microg/ml concentration range, heparin inhibited gene expression and release of FN by 10% fetal calf serum (FCS)-stimulated MC in a concentration-dependent manner. At concentrations of 300 and 1000 microg/ml, heparin inhibited fibronectin mRNA levels in TGF-beta1 (6 ng/ml) stimulated cells. However, heparin had no effect on gene expression or release of collagen IV or laminin under these conditions. Heparin markedly inhibited 10% FCS-stimulated MC proliferation in a concentration-dependent manner.
Conclusions:
Heparin inhibited MC growth and fibronectin production. These effects may, in part, account for the reported beneficial effects of heparin on the course of renal disease in experimental animals.
Insights
Standard heparin inhibits mesangial cell (MC) growth and fibronectin production in vitro. These findings suggest heparin may help treat kidney diseases by reducing MC proliferation and matrix proteins.
Area of Science:
- Nephrology
- Cell Biology
- Pharmacology
Background:
- Mesangial cell (MC) proliferation and matrix expansion are hallmarks of various glomerulopathies.
- Heparin has demonstrated in vitro inhibition of MC proliferation and in vivo mitigation of experimental glomerulonephritis.
- In vitro studies isolate heparin's direct effects on MCs, excluding confounding in vivo factors.
Purpose of the Study:
- To investigate the direct impact of standard heparin on mesangial cell (MC) proliferation in vitro.
- To assess heparin's effect on the gene expression and release of key matrix proteins, including fibronectin (FN), collagen IV, and laminin, by MCs.
- To evaluate the influence of transforming growth factor-beta1 (TGF-beta1) on these matrix protein expressions in the presence of heparin.
Main Methods:
- Cultured rat mesangial cells (MCs) were treated with varying concentrations of heparin (3-1000 microg/ml).
- Gene expression and release of fibronectin (FN), collagen IV, and laminin were measured.
- The effect of TGF-beta1 on matrix protein gene expression was assessed with and without heparin.
Main Results:
- Heparin demonstrated a dose-dependent inhibition of MC proliferation stimulated by 10% fetal calf serum (FCS).
- Heparin significantly reduced gene expression and release of fibronectin (FN) in a concentration-dependent manner.
- Heparin inhibited fibronectin mRNA levels in TGF-beta1-stimulated cells but had no effect on collagen IV or laminin expression.
Conclusions:
- Standard heparin effectively inhibits mesangial cell (MC) proliferation and fibronectin production in vitro.
- These direct cellular effects of heparin may partially explain its previously observed therapeutic benefits in experimental renal diseases.
- Heparin's specific action on fibronectin suggests a targeted mechanism for mitigating matrix expansion in glomerulopathies.