Mitogenic Signaling via Platelet-Derived Growth Factor β in Metanephric Mesenchymal Cells
| Autor: | Karen Block, Yves Gorin, Goutam Ghosh Choudhury, Daniel J. Riley, Brent Wagner, Jill M. Ricono, Mazen Y Arar, Hanna E. Abboud |
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| Rok vydání: | 2007 |
| Předmět: |
Platelet-derived growth factor
medicine.medical_treatment Kidney Glomerulus Cell Culture Techniques Mitosis Mesoderm Receptor Platelet-Derived Growth Factor beta Mice Phosphatidylinositol 3-Kinases chemistry.chemical_compound medicine Animals Protein kinase B Platelet-Derived Growth Factor biology DNA synthesis Growth factor Autophosphorylation NADPH Oxidases General Medicine Cell biology Biochemistry chemistry Nephrology Cell culture biology.protein biological phenomena cell phenomena and immunity Signal transduction Reactive Oxygen Species Platelet-derived growth factor receptor Signal Transduction |
| Zdroj: | Journal of the American Society of Nephrology. 18:2903-2911 |
| ISSN: | 1046-6673 |
| Popis: | Mice deficient in either platelet-derived growth factor (PDGF) B chain or PDGF receptor (PDGFR) beta lack mesangial cells. PDGF stimulates proliferation and migration of metanephric mesenchymal cells, from which mesangial cells are derived. Binding of PDGF to PDGFR-beta induces autophosphorylation at specific tyrosine residues and activates various effector proteins, including phosphatidylinositol-3-kinase (PI3-K). This study explored the role of PI 3-K and reactive oxygen species (ROS) in PDGF-mediated signaling using cells established from wild-type and PDGFR-beta -/- metanephric blastemas at 11.5 days post-conception. PDGF-induced effects that were dependent on PI3-K activation were determined using PDGFR-beta -/- cells made to express "add-back" mutant PDGFR-beta capable of binding PI3-K. We found that PDGF is mitogenic for mesenchymal cells expressing PDGFR-beta, and PI3-K is an important regulator of PDGF-induced DNA synthesis. Activation of ERK1/2 is partially dependent on PI3-K, and both the PI3-K and MEK-ERK1/2 pathways contribute to PI3-K-dependent mitogenesis. In addition, PDGF-induced DNA synthesis in wild-type cells was found to be dependent on ROS that are generated downstream of PI3-K activation. Using antisense oligonucleotides and small interfering RNA, we determined that the NAD(P)H oxidase Nox4 produces these ROS that activate Akt and the MEK-ERK1/2 mitogenic cascade. In conclusion, the present study demonstrates Nox4 involvement in PDGF-induced DNA synthesis in metanephric mesenchymal cells and provides the first evidence that PDGF-induced PI3-K activity enhances production of ROS by Nox4. |
| Databáze: | OpenAIRE |
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