PLATELET-DERIVED GROWTH-FACTOR AND ANGIOTENSIN-II STIMULATE THE MITOGEN-ACTIVATED PROTEIN-KINASE CASCADE IN RENAL MESANGIAL CELLS - COMPARISON OF HYPERTROPHIC AND HYPERPLASTIC AGONISTS

Exposure of mesangial cells to platelet-derived growth factor (PDGF) BE caused a significant stimulation of cell proliferation and protein synthesis, as measured by [H-3]thymidine incorporation and [H-3]leucine incorporation respectively. In contrast, cells treated with angiotensin II had no significant increase in [3H]thymidine incorporation, but demonstrated a marked increase in [H-3]leucine incorporation. Furthermore, angiotensin II significantly increased total protein content per cell. These data show that, whereas PDGF-BB is a mitogen and stimulates mesangial-cell hyperplasia, angiotensin II causes hypertrophy of the cells without hyperplasia. Treatment of mesangial cells with PDGF and angiotensin II rapidly and dose-dependently stimulated mitogen-activated protein (MAP) kinase activity, as shown by an assay for activity in vitro using myelin basic protein as a substrate, and by immunoprecipitation of P-32-labelled cells with specific antibodies against the 42 kDa and 44 kDa mitogen-activated protein kinases p42(mapk) and p44(mapk), respectively. Whereas stimulation with PDGF-BB caused a potent and sustained (for more than 30 min) phosphorylation and activation of p42(mapk) and p44(mapk) as well as of the upstream activators MAP kinase kinase and c-Raf, the effect of angiotensin II was less potent, reaching a peak at 5-10 min and thereafter declining rapidly. In summary, these results suggest that PDGF-BB and angiotensin II differ in their potency and duration of activation of the MAP kinase cascade, which may explain why PDGF-BB is a potent mitogen for mesangial cells, whereas angiotensin II only triggers mesangial-cell hypertrophy.