ET-1 AND PDGF BB INDUCE MEK MESSENGER-RNA AND PROTEIN EXPRESSION IN MESANGIAL CELLS

To evaluate a possible mechanism for the chronic regulation of MAPK/ER K kinase-1 (MEK-1) and p42 mitogen-activated protein kinase (MAPK) we studied the long-term effects of the G-protein-coupled receptor agonis t endothelin-1 (ET-1) and the protein tyrosine kinase-coupled receptor agonist platelet-derived growth factor BB (PDGF BB) on MEK-1 and p42 MAPK in glomerular mesangial cells (GMCs). ET-1 and PDGF BB led to a t ime-dependent increase in MEK-1 mRNA expression without altering p42 M APK mRNA levels. The effect of ET-1 and PDGF BB on MEK-1 mRNA expressi on was maximal after 24 h (3.3-fold) or 6 h (2.9-fold). Furthermore, t he effect of ET-1 and PDGF BB on MEK-1 mRNA expression was additive (4 .2-fold after 6 h) and was inhibited by actinomycin D (5 mu g/ml). Cyc loheximide (10 mu g/ml) inhibited MEK-1 mRNA induction but stimulated p42 MAPK mRNA expression in both the absence and the presence of ET-1 and/or PDGF BB. The ET-1 and PDGF BB-induced increase in MEK-1 mRNA wa s accompanied by sustained enhancement of both p45 MEK protein express ion after 12 h and by elevation of p42 MAPK activity for up to 24 h. W e conclude that, in GMCs, MEK-1 acts like a delayed-early gene, wherea s p42 MAPK resembles an immediate-early gene. MEK-1 mRNA and protein l evels, as well as p42 MAPK activity, can be chronically regulated by b oth a seven-transmembrane domain receptor-coupled peptide such as ET-1 and by an agonist binding to a receptor with intrinsic protein tyrosi ne kinase activity, such as PDGF BB.