| First Author | Wagner B | Year | 2007 |
| Journal | J Am Soc Nephrol | Volume | 18 |
| Issue | 11 | Pages | 2903-11 |
| PubMed ID | 17942966 | Mgi Jnum | J:172977 |
| Mgi Id | MGI:5009390 | Doi | 10.1681/ASN.2006111229 |
| Citation | Wagner B, et al. (2007) Mitogenic signaling via platelet-derived growth factor beta in metanephric mesenchymal cells. J Am Soc Nephrol 18(11):2903-11 |
| abstractText | 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. |
