Phenotypic transformation of normal rat kidney fibroblasts by endothelin-1. Different mode of action from lysophosphatidic acid, bradykinin, and prostaglandin F 2α

• Published in: Biochimica et biophysica acta. Molecular cell research Vol. 1449; no. 2; pp. 107 - 118
• Main Authors: Lahaye, D.H.T.P., Walboomers, F., Peters, P.H.J., Theuvenet, A.P.R., Van Zoelen, E.J.J.
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 1999
• Subjects: Density dependent growth inhibition; Endothelin-1; G protein coupled receptor; Normal rat kidney; Phenotypic transformation; Second messenger; Density dependent growth inhibition; Normal rat kidney; G protein coupled receptor; Endothelin-1; Second messenger; Phenotypic transformation
• ISSN: 0167-4889; 1879-2596
• DOI: 10.1016/S0167-4889(99)00002-6

In the present study, we compared the effects of endothelin (ET)-1 on cell proliferation and second messenger induction in normal rat kidney (NRK) fibroblasts, with those of other activators of G-protein-coupled receptors such as prostaglandin (PG)-F 2α, bradykinin (BK), and lysophosphatidic acid (LPA). LPA is mitogenic by itself, while the other factors require the presence of EGF. In density-arrested NRK cells, ET-1 and LPA induce phenotypic transformation rapidly, with similar kinetics as retinoic acid (RA) and transforming growth factor (TGF)-β, while BK and PGF 2α only do so with delayed kinetics. ET-1 and PGF 2α are strong inducers of anchorage-independent growth, with a similar level of induction as TGFβ, in contrast to LPA and BK. When investigating the second messenger generation, we found that ET-1 is the strongest activator of arachidonic acid release and phosphatidylinositol diphosphate hydrolysis. Only in the case of ET-1 the cell depolarization is not reversible upon removal of the factor. Similarly, only the ET-1-induced transient enhancement of intracellular calcium concentration is paralleled by both homologous and heterologous desensitization. In conclusion, these data show that ET-1 is a potent inducer of second messengers and phenotypic transformation in NRK cells, with characteristics that clearly differ from those of other activators of G-protein-coupled receptors, most likely as a result of prolonged receptor activation.