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

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17 Scopus citations

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)
Pages (from-to)F270-F278
JournalAmerican Journal of Physiology - Renal Physiology
Volume278
Issue number2 47-2
DOIs
StatePublished - Feb 2000

Keywords

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

ASJC Scopus subject areas

  • Physiology
  • Urology

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