PLATELET-DERIVED GROWTH-FACTOR STIMULATES DE-NOVO SYNTHESIS OF MITOGEN-ACTIVATED PROTEIN-KINASE IN RENAL MESANGIAL CELLS

Platelet-derived growth factor (PDGF) BB is a potent mitogen for renal mesangial cells and stimulates a biphasic mitogen-activated protein k inase (MAP kinase) activation. A rapid increase in activity (maximal a t 10 min) is followed by a lower persistent level of activity which is maximal at 4-6 h. The second peak of MAP kinase activity is markedly attenuated by the protein synthesis inhibitor cycloheximide and, conse quently, is paralleled by a marked de-novo synthesis of p42 and p44 MA P kinases, as measured by immunoprecipitation of [S-35]methionine-labe led mesangial cells and by a 700 % increase in total MAP kinase protei n, as detected by Western-blot analysis. A 30-min treatment with PDGF- BB is sufficient to induce pronounced de-novo synthesis of MAP kinase. However, for maximal induction of MAP kinase synthesis, PDGF is requi red to be present for at least 4 h. In addition, an increased de-novo synthesis of MAP kinase kinase, the upstream activator of MAP kinase, is observed in response to PDGF stimulation. We propose that PDGF-indu ced de-novo synthesis of MAP kinase and MAP kinase kinase is important for the potent mitogenic activity of this growth factor.