Phospholipase A2-mediated Activation of Mitogen-Activated Protein Kinase by Angiotensin II

In renal proximal tubule epithelial cells, a membrane-associated phospholipase A2(PLA2) is a major signaling pathway linked to angiotensin II (Ang II) type 2 receptor (AT2). The current studies were designed to test the hypothesis that membrane-associated PLA2-induced release of arachidonic acid (AA...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1998-07, Vol.95 (14), p.8098-8102
Main Authors: Dulin, Nickolai O., Alexander, Larry D., Harwalkar, Subash, Falck, John R., Douglas, Janice G.
Format: Article
Language:English
Subjects:
Angiotensin II - pharmacology
Animals
Antibodies
Biological Sciences
Calcium-Calmodulin-Dependent Protein Kinases - metabolism
Cells, Cultured
Cellular biology
Cellular metabolism
Cytochromes
Enzyme Activation - drug effects
Epithelial cells
Epithelium
Kidney Tubules - metabolism
Kidneys
Male
Phospholipases A - metabolism
Phospholipases A2
Phosphorylation
Protein isoforms
Protein metabolism
Proteins
Proximal tubules
Rabbits
Receptors
Signal Transduction - drug effects
Vasoconstrictor Agents - pharmacology
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Summary:In renal proximal tubule epithelial cells, a membrane-associated phospholipase A2(PLA2) is a major signaling pathway linked to angiotensin II (Ang II) type 2 receptor (AT2). The current studies were designed to test the hypothesis that membrane-associated PLA2-induced release of arachidonic acid (AA) and/or its metabolites may serve as an upstream mediator of Ang II-induced mitogen-activated protein kinase (MAPK) activation. Ang II stimulated transient dose-dependent phosphorylation of MAPK with a maximum at 1 μ M (10 min). Inhibition of PLA2by mepacrine diminished both AA release and MAPK phosphorylation, induced by Ang II. Furthermore, AA itself induced time- and dose-dependent phosphorylation of MAPK, supporting the importance of PLA2as a mediator of Ang II signaling. The effects of both Ang II and AA on MAPK phosphorylation were protein kinase C independent and abolished by the inhibitor of cytochrome P450 isoenzyme, ketoconazole. Moreover, 5,6-epoxyeicosatrienoic acid and 14,15-epoxyeicosatrienoic acid, the cytochrome P450-dependent metabolites of AA, significantly stimulated MAPK activity in renal proximal tubule epithelial cells. These observations document a mechanism of Ang II-induced MAPK phosphorylation, mediated by PLA2-dependent release of AA and cytochrome P450-dependent production of epoxy derivatives of AA.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.95.14.8098