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 fact or beta(2) (TGF beta(2)) stimulates a biphasic mitogen-activated prote in kinase (MAP kinase) activation. A rapid increase in activity (maxim al at 10 min) is followed by a second persistent level of activity whi ch steadily increases over 24 h. The second peak of MAP kinase activit y is markedly attenuated by the protein synthesis inhibitor cyclohexim ide and consequently is paralleled by a pronounced de-novo synthesis o f 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 ki nase, is observed in response to TGF beta(2) stimulation. We propose t hat TGF beta-induced activation and de-novo synthesis of MAP kinases a nd MEK is important for the multifunctional actions of this cytokine i n mesangial cells and its role in disease states characterized by exce ssive fibrosis.