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PMID:17942966

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Citation

Wagner, B, Ricono, JM, Gorin, Y, Block, K, Arar, M, Riley, D, Choudhury, GG and Abboud, HE (2007) Mitogenic signaling via platelet-derived growth factor beta in metanephric mesenchymal cells. J. Am. Soc. Nephrol. 18:2903-11

Abstract

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.

Links

PubMed Online version:10.1681/ASN.2006111229

Keywords

Animals; Cell Culture Techniques; Kidney Glomerulus/embryology; Mesoderm/cytology; Mesoderm/physiology; Mice; Mitosis/physiology; NADPH Oxidase/physiology; Phosphatidylinositol 3-Kinases/physiology; Platelet-Derived Growth Factor/physiology; Reactive Oxygen Species/metabolism; Receptor, Platelet-Derived Growth Factor beta/physiology; Signal Transduction/physiology

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:PDGFB

enables

GO:0016176: superoxide-generating NADPH oxidase activator activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:PDGFB

involved_in

GO:0014068: positive regulation of phosphatidylinositol 3-kinase signaling

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PDGFB

involved_in

GO:0006468: protein phosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PDGFB

involved_in

GO:2000573: positive regulation of DNA biosynthetic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PDGFB

involved_in

GO:0072593: reactive oxygen species metabolic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PDGFB

involved_in

GO:0070374: positive regulation of ERK1 and ERK2 cascade

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PDGFB

involved_in

GO:0045840: positive regulation of mitotic nuclear division

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PDGFB

involved_in

GO:0043406: positive regulation of MAP kinase activity

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PGFRB

involved_in

GO:0014068: positive regulation of phosphatidylinositol 3-kinase signaling

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PGFRB

involved_in

GO:0070374: positive regulation of ERK1 and ERK2 cascade

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PGFRB

involved_in

GO:0045840: positive regulation of mitotic nuclear division

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PGFRB

involved_in

GO:0043406: positive regulation of MAP kinase activity

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:NOX4

enables

GO:0016175: superoxide-generating NAD(P)H oxidase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:NOX4

enables

GO:0016175: superoxide-generating NADPH oxidase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:NOX4

involved_in

GO:0043406: positive regulation of MAP kinase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:NOX4

involved_in

GO:0051897: positive regulation of protein kinase B signaling

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:NOX4

involved_in

GO:0070374: positive regulation of ERK1 and ERK2 cascade

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:NOX4

involved_in

GO:0072593: reactive oxygen species metabolic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:NOX4

involved_in

GO:2000573: positive regulation of DNA biosynthetic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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