Isoproterenol inhibits fibroblast growth factor-2-induced growth of renal epithelial cells

The signal transduction pathways modulating bFGF effects in renal tubular e pithelial cells (RTEc) are not completely understood. Since the cAMP and th e mitogen-activated protein kinase (MAPK) pathways can modulate the growth of RTEc, we studied whether two cAMP elevating agents, isoproterenol and 8- bromo-cAMP, would modulate basic fibroblast growth factor (bFGF) induction of MAPK activity (ERK-2) and cell proliferation in human renal proximal tub ular epithelial cells (RPTEc) and Madin-Darby canine kidney cells (MDCK clo ne (E11)). Isoproterenol, but not bFGF, stimulated cAMP production in RPTEc and MDCKE11 cells. bFGF, isoproterenol, and 8-bromo-cAMP alone increased E RK-2 activity in both cell types. However, isoproterenol and 8-bromo-cAMP p artially inhibited the bFGF induction of ERK-2 activity, but only isoproter enol inhibited the proliferation of both cell types. PD098059 (25 mu M). an inhibitor of MAPK kinase (MEK 1/2). blocked the bFGF mitogenic effects, bu t did not affect the 8-bromo-cAMP-induced mitogenic effects in MDCKE11 cell s. These findings suggest that activation of ERK-2 is required but not suff icient for mitogenesis in RTEc. We conclude that isoproterenol inhibits the growth-promoting effects of bFGF in RTEc via MEK-dependent and -independen t pathways.