TY - JOUR
T1 - Mitogenic signaling via platelet-derived growth factor β in metanephric mesenchymal cells
AU - Wagner, Brent
AU - Ricono, Jill M.
AU - Gorin, Yves
AU - Block, Karen
AU - Arar, Mazen
AU - Riley, Dan
AU - Choudhury, Goutam Ghosh
AU - Abboud, Hanna E.
N1 - Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2007/11
Y1 - 2007/11
N2 - Mice deficient in either platelet-derived growth factor (PDGF) B chain or PDGF receptor (PDGFR) β lack mesangial cells. PDGF stimulates proliferation and migration of metanephric mesenchymal cells, from which mesangial cells are derived. Binding of PDGF to PDGFR-β 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-β -/- metanephric blastemas at 11.5 days post-conception. PDGF-induced effects that were dependent on PI3-K activation were determined using PDGFR-β -/- cells made to express "add-back" mutant PDGFR-" capable of binding PI3-K. We found that PDGF is mitogenic for mesenchymal cells expressing PDGFR-β, 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.
AB - Mice deficient in either platelet-derived growth factor (PDGF) B chain or PDGF receptor (PDGFR) β lack mesangial cells. PDGF stimulates proliferation and migration of metanephric mesenchymal cells, from which mesangial cells are derived. Binding of PDGF to PDGFR-β 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-β -/- metanephric blastemas at 11.5 days post-conception. PDGF-induced effects that were dependent on PI3-K activation were determined using PDGFR-β -/- cells made to express "add-back" mutant PDGFR-" capable of binding PI3-K. We found that PDGF is mitogenic for mesenchymal cells expressing PDGFR-β, 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.
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U2 - 10.1681/ASN.2006111229
DO - 10.1681/ASN.2006111229
M3 - Article
C2 - 17942966
AN - SCOPUS:35848936524
VL - 18
SP - 2903
EP - 2911
JO - Journal of the American Society of Nephrology
JF - Journal of the American Society of Nephrology
SN - 1046-6673
IS - 11
ER -