Faculty Collaboration Database

20-HETE activates the Raf/MEK/ERK pathway in renal epithelial cells through an EGFR- and c-Src-dependent mechanism. Am J Physiol Renal Physiol 2009 Sep;297(3):F662-70

Date

07/03/2009

Pubmed ID

19570883

Pubmed Central ID

PMC2739708

DOI

10.1152/ajprenal.00146.2009

Scopus ID

2-s2.0-69449101237 (requires institutional sign-in at Scopus site)   46 Citations

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.

Author List

Akbulut T, Regner KR, Roman RJ, Avner ED, Falck JR, Park F

Authors

Ellis D. Avner MD Professor in the Pediatrics department at Medical College of Wisconsin
Kevin R. Regner MD Interim Chair, Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Epithelial Cells
ErbB Receptors
Extracellular Signal-Regulated MAP Kinases
Hydroxyeicosatetraenoic Acids
Kidney
LLC-PK1 Cells
Lipopeptides
MAP Kinase Kinase 1
MAP Kinase Kinase 2
Male
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase Kinases
Phosphorylation
Protein Kinase Inhibitors
Proto-Oncogene Proteins c-akt
Proto-Oncogene Proteins c-raf
Proto-Oncogene Proteins pp60(c-src)
Rats
Rats, Sprague-Dawley
Signal Transduction
Swine
Time Factors