TRANSFORMING GROWTH-FACTOR BETA(2) STIMULATES ACUTE AND CHRONIC ACTIVATION OF THE MITOGEN-ACTIVATED PROTEIN-KINASE CASCADE IN RAT RENAL MESANGIAL CELLS

Exposure of rat glomerular mesangial cells to transforming growth factor beta(2) (TGF beta(2)) stimulates a biphasic mitogen-activated protein kinase (MAP kinase) activation. A rapid increase in activity (maximal at 10 min) is followed by a second persistent level of activity which steadily increases over 24 h. The second peak of MAP kinase activity is markedly attenuated by the protein synthesis inhibitor cycloheximide and consequently is paralleled by a pronounced de-novo synthesis of p42 and p44 MAP kinases as measured by immunoprecipitation of [S-35]methionine-labeled mesangial cells. In addition, an increased de-novo synthesis of MAP kinase kinase (MEK), the upstream activator of MAP kinase, is observed in response to TGF beta(2) stimulation. We propose that TGF beta-induced activation and de-novo synthesis of MAP kinases and MEK is important for the multifunctional actions of this cytokine in mesangial cells and its role in disease states characterized by excessive fibrosis.