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Activated coagulation factor X: a novel mitogenic stimulus for human mesangial cells
Raffaella Monno1, Giuseppe Grandaliano1, Roberta Faccio2
1Division of Nephrology, Department of Emergency and Transplantation, University of Bari, Bari, Italy.
Journal of the American Society of Nephrology : JASN
|April 24, 2001
Summary
Activated factor X (FXa) significantly increases human mesangial cell proliferation and platelet-derived growth factor (PDGF) expression. This mitogenic effect involves tyrosine kinase and phospholipase C-protein kinase C pathways, not the effector protease receptor-1.
Area of Science:
- Nephrology
- Cell Biology
- Biochemistry
Background:
- Mesangioproliferative glomerulonephritis involves intraglomerular coagulation activation.
- The cellular effects of coagulation factors beyond thrombin are largely unknown.
Purpose of the Study:
- To investigate the cellular effects of activated factor X (FXa) on human mesangial cells.
- To elucidate the signaling pathways involved in FXa-induced mesangial cell proliferation.
Main Methods:
- Cultured human mesangial cells were treated with FXa.
- DNA synthesis, PDGF gene expression, and intracellular signaling pathways (calcium, tyrosine phosphorylation, MAPK, PKC) were analyzed.
- FXa activity, PDGF, tyrosine kinase, and PKC involvement were assessed using specific inhibitors and antibodies.
Main Results:
- FXa induced dose-dependent DNA synthesis and upregulated PDGF A and B chain expression.
- FXa activated intracellular calcium flux, tyrosine-phosphorylated proteins including c-jun N-terminal kinase.
- FXa-induced proliferation required proteolytic activity, was partially PKC-dependent, and tyrosine kinase activation was PDGF-independent.
Conclusions:
- FXa is a potent mitogen for human mesangial cells.
- FXa mediates its effects via protease-activated receptors, activating phospholipase C-PKC and tyrosine kinase pathways.
- Mesangial cells do not express the effector protease receptor-1 signaling variant.