Endothelin-1 activates MAPKs and modulates cell cycle proteins in OKP cells.
OBJECTIVE
The signaling mechanisms through which endothelin (ET)-1 induces hyperplasia of the renal tubular epithelium are largely unknown.


METHODS
These mechanisms were explored using ETB-overexpressing opossum kidney (OKP) cells as a model system.


RESULTS
ET-1 (10 nM) induced a 10-fold increase in c-jun mRNA abundance within 30 minutes and an 8-fold increase in extracellular signal-regulated kinase (ERK) 1/2 activity within 5-10 minutes in these cells. ERK1/2 phosphorylation in response to ET-1 was suppressed by ETB-receptor blockade or by treatment with an MAPK kinase (MEK) inhibitor. MEK1/2 activity increased 8-fold within 5 minutes of ET-1 treatment. Additionally 2-fold increases in cyclin D1 expression and retinoblastoma (RB) gene product phosphorylation were observed within 4 hours of treatment.


CONCLUSIONS
Binding of ET-1 to the ETB receptor of ETB-overexpressing OKP cells is proposed to signal proliferation of these cells through rapid activation of mitogen-activated protein kinases, increased c-jun expression, modulation of cyclin D1 activity, and increased RB phosphorylation.
Chu
Tzong-Shinn
TS
Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan. tschu@ha.mc.ntu.edu.tw
Wu
Ming-Shiou
MS
Wu
Kwan-Dun
KD
Hsieh
Bor-Shen
BS
D000818:Animals; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology; D007668:Kidney / Q000166:cytology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D009842:Oligopeptides / Q000494:pharmacology; D009893:Opossums; D010456:Peptides, Cyclic / Q000494:pharmacology; D010766:Phosphorylation; D010880:Piperidines / Q000494:pharmacology; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D015398:Signal Transduction
D018797:Cell Cycle Proteins; D019332:Endothelin-1; D005419:Flavonoids; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; D016755:Proto-Oncogene Proteins c-jun; C086539:BQ 788; C072247:cyclo(Trp-Asp-Pro-Val-Leu); C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one