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Mitogenic signaling via platelet-derived growth factor beta in metanephric mesenchymal cells.

Wagner B., Ricono J.M., Gorin Y., Block K., Arar M., Riley D., Choudhury G.G., Abboud H.E.

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.

J. Am. Soc. Nephrol. 18:2903-2911(2007) [PubMed] [Europe PMC]

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