Endothelin-1 activates c-Jun NH2-terminal kinase in mesangial cells.
Endothelin-1 (ET-1) is known to induce the contraction and proliferation of glomerular mesangial cells. ET-1 has been shown to activate p42 and p44 mitogen-activated protein kinases (MAPKs), also known as extracellular signal regulated kinases (ERKs), through both protein kinase C (PKC) and protein tyrosine kinase (PTK)-dependent pathways. However, an involvement of c-Jun NH2-terminal kinase (JNK), one of members of the MAPK family, in ET-1 signaling in mesangial cells has not yet been elucidated. To clarify this point, we examined whether ET-1 could activate JNK and the mechanism of activation in cultured mesangial cells. ET-1 enhanced the activities of JNK in a dose-dependent (10(-8) M maximum) and time-dependent manner, with a peak at 15 minutes. ET-1-induced activation of JNK was blocked by BQ-123, an antagonist for the ETA receptor. The depletion of PKC by prolonged treatment with phorbol 12,13 dibutyrate or the inhibition of PKC by GF 109203X failed to inhibit ET-1-induced activation of JNK. In contrast, ET-1-induced activation of JNK was significantly reduced by calcium chelation (with BAPTA/AM and EGTA). In addition, ionomycin, a calcium ionophore, and thapsigargin, an intracellular calcium-rising agent, were able to induce the activation of JNK. ET-1-induced activation of JNK was also inhibited by PTK inhibitors (herbimycin A and genistein). Furthermore, ET-1 increased the DNA-binding activity of AP-1 containing c-Jun and c-Fos proteins. These results indicate that ET-1 is able to activate JNK in glomerular mesangial cells through PKC-independent and PTK-dependent pathways and intracellular calcium is necessary to the activation of JNK.
Araki
S
S
Third Department of Medicine, Shiga University of Medical Science, Japan.
Haneda
M
M
Togawa
M
M
Kikkawa
R
R
D000818:Animals; D016227:Benzoquinones; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019833:Genistein; D005920:Glomerular Mesangium / Q000187:drug effects* / Q000201:enzymology*; D007529:Isoflavones / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases; D047029:Lactams, Macrocyclic; D020928:Mitogen-Activated Protein Kinases; D010456:Peptides, Cyclic / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011809:Quinones / Q000494:pharmacology; D051381:Rats; D017828:Rifabutin / Q000031:analogs & derivatives; D018808:Transcription Factor AP-1 / Q000378:metabolism
D016227:Benzoquinones; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D007529:Isoflavones; D047029:Lactams, Macrocyclic; D010456:Peptides, Cyclic; D011809:Quinones; D018808:Transcription Factor AP-1; D017828:Rifabutin; C020754:herbimycin; D004247:DNA; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; C072247:cyclo(Trp-Asp-Pro-Val-Leu)