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) 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 microM (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 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.
Dulin
N O
NO
Division of Hypertension, Department of Medicine, Case Western Reserve University School of Medicine/University Hospitals of Cleveland, 10900 Euclid Avenue, Cleveland, OH 44106-4982, USA.
Alexander
L D
LD
Harwalkar
S
S
Falck
J R
JR
Douglas
J G
JG
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D007684:Kidney Tubules / Q000378:metabolism*; D008297:Male; D010741:Phospholipases A / Q000378:metabolism*; D054467:Phospholipases A2; D010766:Phosphorylation; D011817:Rabbits; D015398:Signal Transduction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D010741:Phospholipases A; D054467:Phospholipases A2