title: Differential inhibition of mesangial MAP kinase cascade by cyclic nucleotides.
abstract: The agents which increase intracellular cyclic AMP (cAMP) or cyclic GMP (cGMP) have been found to counteract the effects of the vasoconstrictive agents such as endothelin-1 (ET-1). To clarify the mechanism of this interaction, we evaluated the activities of mitogen-activated protein kinase (MAPK) cascade, one of the important signal transduction system of ET-1. Beraprost sodium, an analogue of PGI2, and adrenomedullin, a cAMP-raising agent, inhibited ET-1-induced activation of MAPK. Dibutyryl cAMP (Bt2-cAMP) and 8-bromo-cGMP (8-Br-cGMP), cell permeable analogues of cAMP and cGMP, were also able to inhibit the activation of MAPK and MAPK kinase (MAPKK) by ET-1 without interfering basal activities. In contrast, phorbol 12, 13-dibutylate (PDBu)-induced activation of MAPK and MAPKK was inhibited by Bt2-cAMP but not by 8-Br-cGMP. Interestingly, atrial natriuretic peptide (ANP) partially inhibited PDBu-induced activation of MAPK and MAPKK. These results indicate that cAMP and cGMP inhibit ET-1-induced activation of MAPK in cultured mesangial cells at different steps; the former might inhibit at a step downstream of PKC and the latter prior to PKC. The data also suggest that ANP might have cGMP-independent effect on MAPK.
authors.affiliation: Third Department of Medicine, Shiga University of Medical Science, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Haneda
authors.forename: S
authors.initials: S
authors.lastname: Araki
authors.forename: T
authors.initials: T
authors.lastname: Sugimoto
authors.forename: M
authors.initials: M
authors.lastname: Togawa
authors.forename: D
authors.initials: D
authors.lastname: Koya
authors.forename: R
authors.initials: R
authors.lastname: Kikkawa
mesh_terms: D053607:Adrenomedullin; D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism / Q000494:pharmacology; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D019332:Endothelin-1 / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D011464:Epoprostenol / Q000031:analogs & derivatives / Q000494:pharmacology; D005920:Glomerular Mesangium / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases; D009712:Nucleotides, Cyclic / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction
chemical_list: D019332:Endothelin-1; D004791:Enzyme Inhibitors; D009712:Nucleotides, Cyclic; D010455:Peptides; D053607:Adrenomedullin; C016276:8-bromocyclic GMP; C048081:beraprost; D015240:Phorbol 12,13-Dibutyrate; D003994:Bucladesine; D011464:Epoprostenol; D000242:Cyclic AMP; D011494:Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D006152:Cyclic GMP