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

Pediatr Nephrol. 2000 Aug;14(8-9):726-34. doi: 10.1007/pl00013426.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 8-Bromo Cyclic Adenosine Monophosphate / pharmacology
  • Animals
  • Cell Division / drug effects
  • Cell Line
  • Cells, Cultured
  • Cyclic AMP / metabolism*
  • Dogs
  • Enzyme Inhibitors / pharmacology
  • Fibroblast Growth Factor 2 / antagonists & inhibitors
  • Fibroblast Growth Factor 2 / pharmacology*
  • Flavonoids / pharmacology
  • Humans
  • Isoproterenol / pharmacology*
  • Kidney / cytology
  • Kidney / drug effects*
  • Kidney / metabolism
  • MAP Kinase Kinase 1
  • MAP Kinase Kinase 2
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Protein Serine-Threonine Kinases / metabolism
  • Protein-Tyrosine Kinases / metabolism
  • Urothelium / cytology
  • Urothelium / drug effects
  • Urothelium / metabolism


  • Enzyme Inhibitors
  • Flavonoids
  • Fibroblast Growth Factor 2
  • 8-Bromo Cyclic Adenosine Monophosphate
  • Cyclic AMP
  • MAP2K2 protein, human
  • Protein-Tyrosine Kinases
  • Protein Serine-Threonine Kinases
  • MAP Kinase Kinase 1
  • MAP Kinase Kinase 2
  • MAP2K1 protein, human
  • Mitogen-Activated Protein Kinase Kinases
  • Isoproterenol
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one