DDM-PGE2-mediated cytoprotection in renal epithelial cells by a thromboxane A2 receptor coupled to NF-κB

Thomas J. Weber, Terrence Monks, Serrine Lau

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17 Citations (Scopus)

Abstract

The present studies were conducted to determine the pharmacological nature of a cytoprotective 11-deoxy-16,16-dimethyl-PGE2 (DDM-PGE2) receptor in LLC-PK1 cells. DDM-PGE2-mediated cytoprotection against 2,3,5- (trisglutathion-S-yl)hydroquinone (TGHQ)-mediated cytotoxicity can be reproduced using thromboxane A2 (TXA2) receptor (TP) agonists (U46619 and IBOP), and the cytoprotective response to DDM-PGE2 and TP agonists is inhibited by TP antagonists (SQ-29,548 and ISAP). Western blot analysis using an antipeptide antibody against the human platelet TP receptor (55 kDa) identified a particulate associated 54-kDa protein. DDMPGE2-mediated 12-O-tetradecanoyl phorbol-13-acetate (TPA) responsive element (TRE) binding activity is not inhibited by cyclooxygenase inhibitors (aspirin and indomethacin) or a TXA2 synthase inhibitor (sulfasalazine), suggesting that the biological response to DDM-PGE2 is not dependent on de novo TXA2 biosynthesis. Peak DDM-PGE2- and U46619-mediated TRE binding activity and nuclear factor-κB (NF-κB) binding activity are inhibited by SQ-29,548. The full cytoprotective response to DDM-PGE2 requires an 8-h pulse with agonist. DDM-PGE2-mediated TRE and NF-κB binding activity remain elevated in the presence of agonist and rapidly decay following agonist washout, suggesting a direct correlation between DDM-PGE2-mediated cytoprotection and persistent DNA binding activities. TPA, a protein kinase C activator, induces cytoprotection and a persistent increase of NF-κB binding activity. DDM-PGE2-mediated cytoprotection and NF-κB binding activity but not TRE binding activity are inhibited by sulfasalazine. We conclude that the DDM- PGE2 receptor is a TP receptor and that the cytoprotective response may be mediated in part by NF-κB.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Renal Physiology
Volume278
Issue number2 47-2
StatePublished - Feb 2000
Externally publishedYes

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Prostaglandin H2 Receptors Thromboxane A2
Cytoprotection
Epithelial Cells
Kidney
Prostaglandin E Receptors
Thromboxane Receptors
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
Sulfasalazine
Thromboxane A2
Tetradecanoylphorbol Acetate
LLC-PK1 Cells
11-deoxy,16,16-dimethyl prostaglandin E(2)
Cyclooxygenase Inhibitors
Indomethacin
Protein Kinase C
Aspirin
Blood Platelets
Western Blotting
Pharmacology

Keywords

  • Kidney
  • Protein kinase C
  • Quinone-thioether
  • TP receptor

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

Cite this

@article{8e7e1bcec1974f14b6a649a5c9343447,
title = "DDM-PGE2-mediated cytoprotection in renal epithelial cells by a thromboxane A2 receptor coupled to NF-κB",
abstract = "The present studies were conducted to determine the pharmacological nature of a cytoprotective 11-deoxy-16,16-dimethyl-PGE2 (DDM-PGE2) receptor in LLC-PK1 cells. DDM-PGE2-mediated cytoprotection against 2,3,5- (trisglutathion-S-yl)hydroquinone (TGHQ)-mediated cytotoxicity can be reproduced using thromboxane A2 (TXA2) receptor (TP) agonists (U46619 and IBOP), and the cytoprotective response to DDM-PGE2 and TP agonists is inhibited by TP antagonists (SQ-29,548 and ISAP). Western blot analysis using an antipeptide antibody against the human platelet TP receptor (55 kDa) identified a particulate associated 54-kDa protein. DDMPGE2-mediated 12-O-tetradecanoyl phorbol-13-acetate (TPA) responsive element (TRE) binding activity is not inhibited by cyclooxygenase inhibitors (aspirin and indomethacin) or a TXA2 synthase inhibitor (sulfasalazine), suggesting that the biological response to DDM-PGE2 is not dependent on de novo TXA2 biosynthesis. Peak DDM-PGE2- and U46619-mediated TRE binding activity and nuclear factor-κB (NF-κB) binding activity are inhibited by SQ-29,548. The full cytoprotective response to DDM-PGE2 requires an 8-h pulse with agonist. DDM-PGE2-mediated TRE and NF-κB binding activity remain elevated in the presence of agonist and rapidly decay following agonist washout, suggesting a direct correlation between DDM-PGE2-mediated cytoprotection and persistent DNA binding activities. TPA, a protein kinase C activator, induces cytoprotection and a persistent increase of NF-κB binding activity. DDM-PGE2-mediated cytoprotection and NF-κB binding activity but not TRE binding activity are inhibited by sulfasalazine. We conclude that the DDM- PGE2 receptor is a TP receptor and that the cytoprotective response may be mediated in part by NF-κB.",
keywords = "Kidney, Protein kinase C, Quinone-thioether, TP receptor",
author = "Weber, {Thomas J.} and Terrence Monks and Serrine Lau",
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language = "English (US)",
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journal = "American Journal of Physiology",
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T1 - DDM-PGE2-mediated cytoprotection in renal epithelial cells by a thromboxane A2 receptor coupled to NF-κB

AU - Weber, Thomas J.

AU - Monks, Terrence

AU - Lau, Serrine

PY - 2000/2

Y1 - 2000/2

N2 - The present studies were conducted to determine the pharmacological nature of a cytoprotective 11-deoxy-16,16-dimethyl-PGE2 (DDM-PGE2) receptor in LLC-PK1 cells. DDM-PGE2-mediated cytoprotection against 2,3,5- (trisglutathion-S-yl)hydroquinone (TGHQ)-mediated cytotoxicity can be reproduced using thromboxane A2 (TXA2) receptor (TP) agonists (U46619 and IBOP), and the cytoprotective response to DDM-PGE2 and TP agonists is inhibited by TP antagonists (SQ-29,548 and ISAP). Western blot analysis using an antipeptide antibody against the human platelet TP receptor (55 kDa) identified a particulate associated 54-kDa protein. DDMPGE2-mediated 12-O-tetradecanoyl phorbol-13-acetate (TPA) responsive element (TRE) binding activity is not inhibited by cyclooxygenase inhibitors (aspirin and indomethacin) or a TXA2 synthase inhibitor (sulfasalazine), suggesting that the biological response to DDM-PGE2 is not dependent on de novo TXA2 biosynthesis. Peak DDM-PGE2- and U46619-mediated TRE binding activity and nuclear factor-κB (NF-κB) binding activity are inhibited by SQ-29,548. The full cytoprotective response to DDM-PGE2 requires an 8-h pulse with agonist. DDM-PGE2-mediated TRE and NF-κB binding activity remain elevated in the presence of agonist and rapidly decay following agonist washout, suggesting a direct correlation between DDM-PGE2-mediated cytoprotection and persistent DNA binding activities. TPA, a protein kinase C activator, induces cytoprotection and a persistent increase of NF-κB binding activity. DDM-PGE2-mediated cytoprotection and NF-κB binding activity but not TRE binding activity are inhibited by sulfasalazine. We conclude that the DDM- PGE2 receptor is a TP receptor and that the cytoprotective response may be mediated in part by NF-κB.

AB - The present studies were conducted to determine the pharmacological nature of a cytoprotective 11-deoxy-16,16-dimethyl-PGE2 (DDM-PGE2) receptor in LLC-PK1 cells. DDM-PGE2-mediated cytoprotection against 2,3,5- (trisglutathion-S-yl)hydroquinone (TGHQ)-mediated cytotoxicity can be reproduced using thromboxane A2 (TXA2) receptor (TP) agonists (U46619 and IBOP), and the cytoprotective response to DDM-PGE2 and TP agonists is inhibited by TP antagonists (SQ-29,548 and ISAP). Western blot analysis using an antipeptide antibody against the human platelet TP receptor (55 kDa) identified a particulate associated 54-kDa protein. DDMPGE2-mediated 12-O-tetradecanoyl phorbol-13-acetate (TPA) responsive element (TRE) binding activity is not inhibited by cyclooxygenase inhibitors (aspirin and indomethacin) or a TXA2 synthase inhibitor (sulfasalazine), suggesting that the biological response to DDM-PGE2 is not dependent on de novo TXA2 biosynthesis. Peak DDM-PGE2- and U46619-mediated TRE binding activity and nuclear factor-κB (NF-κB) binding activity are inhibited by SQ-29,548. The full cytoprotective response to DDM-PGE2 requires an 8-h pulse with agonist. DDM-PGE2-mediated TRE and NF-κB binding activity remain elevated in the presence of agonist and rapidly decay following agonist washout, suggesting a direct correlation between DDM-PGE2-mediated cytoprotection and persistent DNA binding activities. TPA, a protein kinase C activator, induces cytoprotection and a persistent increase of NF-κB binding activity. DDM-PGE2-mediated cytoprotection and NF-κB binding activity but not TRE binding activity are inhibited by sulfasalazine. We conclude that the DDM- PGE2 receptor is a TP receptor and that the cytoprotective response may be mediated in part by NF-κB.

KW - Kidney

KW - Protein kinase C

KW - Quinone-thioether

KW - TP receptor

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