PDGF receptor-{beta} modulates metanephric mesenchyme chemotaxis induced by PDGF AA.
PDGF B chain or PDGF receptor (PDGFR)-beta-deficient (-/-) mice lack mesangial cells. To study responses of alpha- and beta-receptor activation to PDGF ligands, metanephric mesenchymal cells (MMCs) were established from embryonic day E11.5 wild-type (+/+) and -/- mouse embryos. PDGF BB stimulated cell migration in +/+ cells, whereas PDGF AA did not. Conversely, PDGF AA was chemotactic for -/- MMCs. The mechanism by which PDGFR-beta inhibited AA-induced migration was investigated. PDGF BB, but not PDGF AA, increased intracellular Ca(2+) and the production of reactive oxygen species (ROS) in +/+ cells. Transfection of -/- MMCs with the wild-type beta-receptor restored cell migration and ROS generation in response to PDGF BB and inhibited AA-induced migration. Inhibition of Ca(2+) signaling facilitated PDGF AA-induced chemotaxis in the wild-type cells. The antioxidant N-acetyl-l-cysteine (NAC) or the NADPH oxidase inhibitor diphenyleneiodonium (DPI) abolished the BB-induced increase in intracellular Ca(2+) concentration, suggesting that ROS act as upstream mediators of Ca(2+) in suppressing PDGF AA-induced migration. These data indicate that ROS and Ca(2+) generated by active PDGFR-beta play an essential role in suppressing PDGF AA-induced migration in +/+ MMCs. During kidney development, PDGFR beta-mediated ROS generation and Ca(2+) influx suppress PDGF AA-induced chemotaxis in metanephric mesenchyme.
Ricono
Jill M
JM
Department of Molecular Medicine, Institute of Biotechnology, Univ. of Texas Health Science Center at San Antonio, San Antonio, TX 78229-3900, USA.
Wagner
Brent
B
Gorin
Yves
Y
Arar
Mazen
M
Kazlauskas
Andrius
A
Choudhury
Goutam Ghosh
GG
Abboud
Hanna E
HE
D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D002478:Cells, Cultured; D002633:Chemotaxis; D004247:DNA / Q000096:biosynthesis; D007668:Kidney / Q000196:embryology*; D008648:Mesoderm / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D020033:Protein Isoforms / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
D010982:Platelet-Derived Growth Factor; D020033:Protein Isoforms; D017382:Reactive Oxygen Species; C075278:platelet-derived growth factor A; D004247:DNA; D019869:Phosphatidylinositol 3-Kinases; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020797:Receptor, Platelet-Derived Growth Factor beta; D002118:Calcium