Cyclic nucleotides attenuate endothelin-1-induced activation of mitogen-activated protein kinase in cultured rat mesangial cells.
In order to clarify the mechanisms of interaction between endothelin-1 (ET-1) and cyclic AMP (cAMP) or cyclic GMP (cGMP), we examined the effects of cAMP or cGMP on ET-1-induced activation of mitogen-activated protein kinase (MAPK), one of the key enzymes in the signal transduction of ET-1, in cultured rat mesangial cells. ET-1 was able to activate both p42 and p44 MAP kinases in a dose-dependent manner. Cell permeable analogues of cAMP and cGMP, dibutylyl cAMP (BT2-cAMP) and 8 bromo cGMP (8br-GMP), significantly inhibited ET-1-induced activation of MAPK. Atrial natriuretic peptide (ANP), which increased cellular cGMP, was able to inhibit ET-1-induced activation of MAPK in a dose-dependent manner, while c-ANP, an analogue specific to the clearance receptors of ANP, exerted no effect. These results indicate that cAMP and cGMP could modulate the action of ET-1 in mesangial cells at a step of the activation of MAPK.
Sugimoto
T
T
Third Department of Medicine, Shiga University of Medical Science, Japan.
Kikkawa
R
R
Haneda
M
M
Araki
S
S
Koya
D
D
Togawa
M
M
Shigeta
Y
Y
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000494:pharmacology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000494:pharmacology*; D006152:Cyclic GMP / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D016232:Endothelins / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D005920:Glomerular Mesangium / Q000201:enzymology*; D007527:Isoenzymes / Q000187:drug effects / Q000378:metabolism; D007700:Kinetics; D008297:Male; D008970:Molecular Weight; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction
D016232:Endothelins; D007527:Isoenzymes; D009320:Atrial Natriuretic Factor; D000242:Cyclic AMP; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D006152:Cyclic GMP