Hypertonic induction of COX-2 expression in renal medullary epithelial cells requires transactivation of the EGFR

Hongyu Zhao, Wei Tian, Cynthia Tai, David Cohen

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Hypertonic stress increases expression of cyclooxygenase-2 (COX-2) in renal medullary epithelial and interstitial cells. Because hypertonic COX-2 expression is, in part, sensitive to inhibition of the ERK MAPK, an effector of activated receptor tyrosine kinases such as the EGF receptor, we investigated a role for this receptor in signaling to COX-2 expression. Hypertonic stress increased COX-2 expression at the mRNA and protein levels at 6 and 24 h of hypertonic treatment. Two potent, specific inhibitors of the EGF receptor kinase, AG-1478 and PD-153035, abrogated this effect. These inhibitors also blocked the ability of hypertonic stress to increase PGE2 release; in addition, they partially blocked tonicity-dependent phosphorylation of ERK but not of the related MAPKs, JNK or p38. Pharmacological inhibition of ERK activation partially blocked tonicity-dependent COX-2 expression. Hypertonic induction of COX-2 was likely transcriptionally mediated, as NaCl stress increased luciferase reporter gene activity under control of the human COX-2 promoter, and this effect was also sensitive to inhibition of the EGF receptor kinase. Metalloproteinase action is required for transactivation of the EGF receptor. Pharmacological inhibition of metalloproteinase function blocked tonicity-inducible COX-2 expression. Furthermore, the effect of hypertonicity on COX-2 expression was also evident in the EGF-responsive Madin-Darby canine kidney and 3T3 cell lines but was virtually absent from the EGF-unresponsive (and EGF receptor null) Chinese hamster-derived CHO cell line. Taken together, these data indicate that hypertonicity-dependent COX-2 expression in medullary epithelial cells requires transactivation of the EGF receptor and, potentially, ectodomain cleavage of an EGF receptor ligand.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Renal Physiology
Volume285
Issue number2 54-2
StatePublished - Aug 1 2003

Fingerprint

Cyclooxygenase 2
Transcriptional Activation
Epithelial Cells
Kidney
Epidermal Growth Factor Receptor
Osmotic Pressure
Metalloproteases
Epidermal Growth Factor
Phosphotransferases
Pharmacology
Cell Line
3T3 Cells
Madin Darby Canine Kidney Cells
CHO Cells
Receptor Protein-Tyrosine Kinases
Cricetulus
Luciferases
Reporter Genes
Dinoprostone
Phosphorylation

Keywords

  • Cylooxygenase
  • Heparin-binding epidermal growth factor
  • Hypertonicity
  • Kidney

ASJC Scopus subject areas

  • Physiology

Cite this

Hypertonic induction of COX-2 expression in renal medullary epithelial cells requires transactivation of the EGFR. / Zhao, Hongyu; Tian, Wei; Tai, Cynthia; Cohen, David.

In: American Journal of Physiology - Renal Physiology, Vol. 285, No. 2 54-2, 01.08.2003.

Research output: Contribution to journalArticle

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