Background/purpose: 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.
Conclusion: 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.