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Caveolin-1 in mesangial cells suppresses MAP kinase activation and cell proliferation induced by bFGF and PDGF
Yutaka Fujita1, Shoichi Maruyama, Hiroshi Kogo
1Division of Clinical Immunology, Department of Internal Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan. fyutaka@med.nagoya-u.ac.jp
Background:
Caveolin is a principal component of caveolae and regulates signaling in caveolae. Mesangial cells contain many caveolae, and thus manipulation of caveolin-1 expression level might be useful to control mesangial cell proliferation, which is an important aggravating factor in many renal diseases.
Methods:
In the present study, we transfected caveolin-1 cDNA to rat primary mesangial cells and MES13 cells, and examined the effects on Raf-extracellular signal-regulated protein kinase (ERK) kinase (MEK)-mitogen-activated protein (MAP) kinase pathway and cell proliferation stimulated by basic fibroblast growth factor (bFGF) and platelet-derived growth factor (PDGF). Activity of the kinases was analyzed by immunofluorescence labeling and Western blot analysis.
Results:
The overexpression of caveolin-1 inhibited the activation of Raf-1, MEK-1/2, and MAP kinase induced by either bFGF or PDGF. Furthermore, it suppressed the cell proliferation caused by the cytokines. The effect was specific to the Raf-MEK-MAP kinase pathway, because it did not influence activation of Smad2 induced by transforming growth factor-beta (TGF-beta). On the contrary, expression of a dominant-negative caveolin mutant, DGV-caveolin, augmented activation of MAP kinase.
Conclusion:
The result showed that overexpression of caveolin-1 in mesangial cells suppresses MAP kinase activation and cell proliferation induced by bFGF and PDGF. Because bFGF and PDGF are two major cytokines involved in the mesangioproliferative nephritis, the result implies that introduction of caveolin-1 expression vector is a potential therapeutic tool for the disease.
Insights
Overexpressing caveolin-1 in mesangial cells inhibits the MAP kinase pathway and cell proliferation. This suggests caveolin-1 gene therapy could treat mesangioproliferative nephritis by blocking growth factors.
Area of Science:
- Cell Biology
- Molecular Biology
- Renal Disease Research
Background:
- Caveolin-1 is a key protein in caveolae, regulating cellular signaling.
- Mesangial cells, crucial in renal function, possess abundant caveolae.
- Modulating caveolin-1 levels may control mesangial cell proliferation, a factor in kidney diseases.
Purpose of the Study:
- To investigate the effect of caveolin-1 on the Raf-MEK-MAP kinase pathway.
- To determine caveolin-1's impact on mesangial cell proliferation stimulated by growth factors.
- To explore caveolin-1 as a potential therapeutic target for renal diseases.
Main Methods:
- Transfection of caveolin-1 cDNA into rat primary mesangial cells and MES13 cells.
- Analysis of Raf-extracellular signal-regulated protein kinase (ERK) kinase (MEK)-mitogen-activated protein (MAP) kinase pathway activation via immunofluorescence and Western blot.
- Assessment of cell proliferation in response to basic fibroblast growth factor (bFGF) and platelet-derived growth factor (PDGF).
Main Results:
- Overexpression of caveolin-1 suppressed bFGF- and PDGF-induced activation of Raf-1, MEK-1/2, and MAP kinase.
- Caveolin-1 overexpression inhibited mesangial cell proliferation stimulated by bFGF and PDGF.
- The inhibitory effect was specific to the Raf-MEK-MAP kinase pathway, as Smad2 activation by TGF-beta was unaffected.
Conclusions:
- Caveolin-1 overexpression in mesangial cells effectively suppresses MAP kinase activation and cell proliferation.
- bFGF and PDGF are key cytokines in mesangioproliferative nephritis.
- Introducing a caveolin-1 expression vector presents a potential therapeutic strategy for mesangioproliferative nephritis.
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