Isoproterenol inhibits fibroblast growth factor-2-induced growth of renal epithelial cells.
The signal transduction pathways modulating bFGF effects in renal tubular epithelial cells (RTEc) are not completely understood. Since the cAMP and the 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 tubular epithelial cells (RPTEc) and Madin-Darby canine kidney cells (MDCK clone EI1). Isoproterenol, but not bFGF, stimulated cAMP production in RPTEc and MDCKEI1 cells. bFGF, isoproterenol, and 8-bromo-cAMP alone increased ERK-2 activity in both cell types. However, isoproterenol and 8-bromo-cAMP partially inhibited the bFGF induction of ERK-2 activity, but only isoproterenol inhibited the proliferation of both cell types. PD098059 (25 microM), an inhibitor of MAPK kinase (MEK 1/2), blocked the bFGF mitogenic effects, but did not affect the 8-bromo-cAMP-induced mitogenic effects in MDCKEI1 cells. These findings suggest that activation of ERK-2 is required but not sufficient for mitogenesis in RTEc. We conclude that isoproterenol inhibits the growth-promoting effects of bFGF in RTEc via MEK-dependent and -independent pathways.
Izevbigie
E B
EB
Children's Research Institute, Children's National Medical Center, The George Washington University, Washington, DC 20010, USA.
Gutkind
J S
JS
Ray
P E
PE
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism*; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology*; D007668:Kidney / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D019459:Urothelium / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
D004791:Enzyme Inhibitors; D005419:Flavonoids; D016222:Fibroblast Growth Factor 2; D015124:8-Bromo Cyclic Adenosine Monophosphate; D000242:Cyclic AMP; C482128:MAP2K2 protein, human; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases; D007545:Isoproterenol; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one