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Heparin suppresses mesangial cell proliferation and matrix expansion in experimental mesangioproliferative
Abstract:
Proliferation and extracellular matrix (ECM) overproduction by glomerular mesangial cells characterizes many types of glomerulonephritis and often precedes the development of glomerulosclerosis. Heparin is a potent inhibitor of mesangial cell growth in vitro. We examined whether standard heparin can inhibit mesangial cell proliferation in vivo in the mesangioproliferative anti-Thy 1.1 nephritis. Untreated control rats were compared to rats infused with heparin either early (day -2 to 1) or late (day 2 to 5) after induction of anti-Thy 1.1 nephritis. The results show that heparin treatment significantly reduced mesangial cell proliferation regardless of when it was initiated. Heparin (either early or late treatment) also reduced mesangial basic fibroblast growth factor (bFGF) expression and platelet-derived growth factor (PDGF) receptor up-regulation as reflected by immunostaining, whereas PDGF B-chain expression was reduced only by late heparin treatment. Furthermore, heparin treatment markedly inhibited the mesangial matrix expansion for a variety of ECM proteins, including laminin, type I and IV collagen, fibronectin and entactin. Heparin did not affect the initial mesangiolysis, glomerular macrophage influx, deposition of anti-Thy 1.1 IgG or fibrinogen, or the glomerular platelet influx. These results suggest that heparin, via its antiproliferative rather than anticoagulant effect, can inhibit mesangial cell proliferation, overexpression of polypeptide growth factors, and ECM protein overproduction in vivo. The beneficial effect of heparin can be demonstrated even if treatment is initiated after the development of nephritis. By virtue of these properties, heparin may be an effective agent in the treatment of human mesangioproliferative disease and in the prevention of glomerulosclerosis.
Insights
Standard heparin effectively inhibits mesangial cell proliferation and extracellular matrix overproduction in vivo, offering potential for treating glomerulonephritis and preventing glomerulosclerosis.
Area of Science:
- Nephrology
- Cell Biology
- Pharmacology
Background:
- Glomerulonephritis involves mesangial cell proliferation and extracellular matrix (ECM) overproduction, often leading to glomerulosclerosis.
- Heparin demonstrates in vitro inhibition of mesangial cell growth.
Purpose of the Study:
- To investigate the in vivo efficacy of standard heparin in inhibiting mesangial cell proliferation in anti-Thy 1.1 nephritis.
- To assess heparin's impact on growth factor expression and ECM accumulation in this nephritis model.
Main Methods:
- Rats with anti-Thy 1.1 nephritis were treated with heparin early or late after disease induction.
- Mesangial cell proliferation, growth factor expression (bFGF, PDGF), and ECM protein deposition were evaluated via immunostaining.
Main Results:
- Heparin significantly reduced mesangial cell proliferation irrespective of treatment timing.
- Heparin decreased mesangial basic fibroblast growth factor (bFGF) and platelet-derived growth factor (PDGF) receptor expression.
- Marked inhibition of ECM protein (laminin, collagen, fibronectin, entactin) expansion was observed with heparin treatment.
Conclusions:
- Heparin's antiproliferative effects, not anticoagulant properties, inhibit mesangial cell proliferation and ECM overproduction in vivo.
- Therapeutic benefits of heparin were evident even when initiated after nephritis onset.
- Heparin shows promise for treating human mesangioproliferative diseases and preventing glomerulosclerosis.