PDGF receptor- β modulates metanephric mesenchyme chemotaxis induced by PDGF AA

PDGF B chain or PDGF receptor (PDGFR)-β-deficient (-/-) mice lack mesangial cells. To study responses of α- and β-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-β inhibited AA-induced migration was investigated. PDGF BB, but not PDGF AA, increased intracellular Ca²⁺ and the production of reactive oxygen species (ROS) in +/+ cells. Transfection of -/- MMCs with the wild-type β-receptor restored cell migration and ROS generation in response to PDGF BB and inhibited AA-induced migration. Inhibition of Ca²⁺ 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 Ca²⁺ concentration, suggesting that ROS act as upstream mediators of Ca²⁺ in suppressing PDGF AA-induced migration. These data indicate that ROS and Ca²⁺ generated by active PDGFR-β play an essential role in suppressing PDGF AA-induced migration in +/+ MMCs. During kidney development, PDGFR β-mediated ROS generation and Ca²⁺ influx suppress PDGF AA-induced chemotaxis in metanephric mesenchyme.