NDLI: 20-HETE activates the Raf/MEK/ERK pathway in renal epithelial cells through an EGFR- and c-Src-dependent mechanism.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Akbulut, Talha Regner, Kevin R. Roman, Richard J. Avner, Ellis D. Falck, John R. Park, Frank
Description	Country affiliation: United States Author Affiliation: Akbulut T ( Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.)
Abstract	20-Hydroxyeicosatetraenoic acid (20-HETE) has been reported to promote mitogenicity in a variety of cell types, including renal epithelial cells. However, the signal transduction pathways activated by 20-HETE have not been fully defined. The present study evaluated the effects of 20-HETE and its more stable agonist analogs 20-hydroxyeicosa-5(Z),14(Z)-dienoic acid (5,14-20-HEDE) and N-[20-hydroxyeicosa-5(Z),14(Z)-dienoyl]glycine (5,14-20-HEDGE) on the Raf/MEK/ERK and phosphatidylinositol 3-kinase (PI3K)-Akt pathway in LLC-PK(1) renal epithelial cells. 20-HETE (20 microM) increased phosphorylation of Raf-1 (2.5 +/- 0.2-fold), MEK1/2 (6.3 +/- 1.6-fold), and ERK1/2 (5.8 +/- 0.3-fold) compared with vehicle-treated cells. Similarly, the 20-HETE analogs also strongly activated ERK1/2 in a Raf-1- and MEK1/2-dependent manner. Moreover, 5,14-20-HEDE increased Akt phosphorylation by 2.2 +/- 0.3-fold. 20-HETE and 5,14-20-HEDE also promoted activation (Y1086) of epidermal growth factor receptor (EGFR; Y1086) by 1.9 +/- 0.2- and 2.5 +/- 0.2-fold, respectively. These effects were completely blocked by the EGFR inhibitor EKB-569 (0.1 microM). Moreover, EKB-569 (0.1 microM), as well as a c-Src inhibitor, SKI-606 (0.05 microM), completely abolished the 20-HETE-mediated activation of the Raf/MEK/ERK and PI3K-Akt pathways. Blockade of PKC with bisindolylmaleimide I had no effect on 20-HETE-induced ERK1/2 activation. This study demonstrated that 20-HETE activated the Raf/MEK/ERK and Akt pathways in renal epithelial cells secondary to the activation of c-Src and EGFR.
File Format	HTM / HTML
ISSN	1931857X
e-ISSN	15221466
DOI	10.1152/ajprenal.00146.2009
Journal	AJP: Renal Physiology
Issue Number	3
Volume Number	297
Language	English
Publisher	American Physiological Society
Publisher Date	2009-09-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Research Support, N.i.h., Extramural Research Support, Non-u.s. Gov't Phosphorylation Hydroxyeicosatetraenoic Acids Kidney Antagonists & Inhibitors Proto-oncogene Proteins Pp60(c-src) Discipline Physiology Llc-pk1 Cells Time Factors Swine Extracellular Signal-regulated Map Kinases Proto-oncogene Proteins C-akt Signal Transduction Mitogen-activated Protein Kinase 3 Mitogen-activated Protein Kinase 1 Rats, Sprague-dawley Discipline Nephrology Epithelial Cells Pharmacology Metabolism Drug Effects Protein Kinase Inhibitors Proto-oncogene Proteins C-raf Animals Map Kinase Kinase 2 Map Kinase Kinase 1 Mitogen-activated Protein Kinase Kinases Enzymology Lipopeptides Receptor, Epidermal Growth Factor
Content Type	Text
Resource Type	Article
Subject	Physiology Urology

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