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Mitogenic Signaling via Platelet-Derived Growth Factor in Metanephric Mesenchymal Cells

Brent Wagner^*, Jill M. Ricono^*,, Yves Gorin^*, Karen Block^*, Mazen Arar, Dan Riley^*,, Goutam Ghosh Choudhury^*, and Hanna E. Abboud^*,

Departments of ^* Medicine; and Pediatrics, University of Texas Health Science Center; Department of Molecular Medicine, Institute of Biotechnology; and the Geriatric Research Education and Clinical Center, South Texas Veterans Health Care System, San Antonio, Texas

Correspondence: Dr. Brent Wagner, Division of Nephrology, Department of Medicine, UTHSCSA, 7703 Floyd Curl Drive, MC 7882, San Antonio, TX 78229-3900. Phone: 210-567-2917; Fax: 210-567-4731; E-mail: wagnerb{at}uthscsa.edu

Received for publication November 10, 2006. Accepted for publication June 14, 2007.

Mice deficient in either platelet-derived growth factor (PDGF) B chain or PDGF receptor (PDGFR) lack mesangial cells. PDGF stimulates proliferation and migration of metanephric mesenchymal cells, from which mesangial cells are derived. Binding of PDGF to PDGFR- 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- –/– metanephric blastemas at 11.5 days post-conception. PDGF-induced effects that were dependent on PI3-K activation were determined using PDGFR- –/– cells made to express "add-back" mutant PDGFR- capable of binding PI3-K. We found that PDGF is mitogenic for mesenchymal cells expressing PDGFR-, 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.

Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673