Phospholipase A2-mediated activation of mitogen-activated protein kinase by angiotensin II

Nickolai O. Dulin, Larry D. Alexander, Subash Harwalkar, John R. Falck, Janice G. Douglas

Research output: Contribution to journalArticle

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Abstract

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 μM (10 min). Inhibition of PLA2 by 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 PLA2 as a mediator of Ang II signaling. The effects of both Ang II and AA on MAPK phosphorylation were protein kinasc 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.

Original languageEnglish (US)
Pages (from-to)8098-8102
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume95
Issue number14
DOIs
StatePublished - Jul 7 1998

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