Faculty Collaboration Database

Role of tyrosine kinase and PKC in the vasoconstrictor response to 20-HETE in renal arterioles. Hypertension 1999 Jan;33(1 Pt 2):414-8

Date

02/04/1999

Pubmed ID

9931139

DOI

10.1161/01.hyp.33.1.414

Scopus ID

2-s2.0-0032946311 (requires institutional sign-in at Scopus site)   113 Citations

Abstract

The present study examined the hypothesis that activation of protein kinase C (PKC), components of the mitogen-activated protein (MAP) kinase pathway, or both contributes to the inhibitory effects of 20-hydroxyeicosatetraenoic acid (20-HETE) on K+-channel activity and its vasoconstrictor response in renal arterioles. 20-HETE (0.1 to 50 micromol/L) dose-dependently produced a 30% increase in PKC activity and a fivefold rise in the expression of active extracellular signal-regulated kinase 1 (ERK1) and ERK2 proteins in renal microvessels. 20-HETE (0.01 to 1 micromol/L) reduced the diameter of isolated perfused renal interlobular arterioles by 33+/-2%. Blockade of PKC activity with an N-myristoylated PKC pseudosubstrate inhibitor (Myr-PKCi, 100 micromol/L) or calphostin C (0.5 micromol/L) had no significant effect on the vasoconstrictor response to 20-HETE. In contrast, the tyrosine kinase inhibitors genistein (30 micromol/L) and tyrphostin 25 (10 micromol/L) reduced the response to 20-HETE by 76.5+/-2.1% and 67.5+/-1.8%, respectively. A specific inhibitor of mitogen-activated extracellular signal-regulated kinase (MEK), PD98059, had no effect on the vasoconstrictor response to 20-HETE. In cell-attached patches on renal vascular smooth muscle cells, 20-HETE reduced the open state probability of a large-conductance K+ channel (from 0.0026+/-0.0004 to 0.0006+/-0.0001). The Myr-PKCi (100 micromol/L) did not alter the inhibitory effects of 20-HETE on this channel. In contrast, the tyrosine kinase inhibitor genistein (30 micromol/L) blocked the inhibitory effects of 20-HETE on the large-conductance K+ channel. These data suggest that 20-HETE activates the MAP kinase system in renal arterioles and that the activation of a tyrosine kinase, which is proximal to MEK in this cascade, contributes to the inhibitory effects of 20-HETE on K+-channel activity and its vasoconstrictor effects in the renal arterioles.

Author List

Sun CW, Falck JR, Harder DR, Roman RJ

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

Animals
Arterioles
Calcium-Calmodulin-Dependent Protein Kinases
Dose-Response Relationship, Drug
Hydroxyeicosatetraenoic Acids
In Vitro Techniques
Kidney Glomerulus
Kinetics
Male
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinases
Muscle, Smooth, Vascular
Patch-Clamp Techniques
Potassium Channels
Protein Kinase C
Protein-Tyrosine Kinases
Rats
Rats, Sprague-Dawley
Renal Circulation
Signal Transduction
Vasoconstriction