Urea signalling to immediate-early gene transcription in renal medullary cells requires transactivation of the epidermal growth factor receptor

Hongyu Zhao, Wei Tian, Hongshi Xu, David Cohen

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Signalling by physiological levels of urea (e.g. 200 mM) in cells of the mammalian renal medulla is reminiscent of activation of a receptor tyrosine kinase. The epidermal growth factor (EGF) receptor may be transactivated by a variety of G-protein-coupled receptors, primarily through metalloproteinase-dependent cleavage of a membrane-anchored EGF precursor. In the murine inner medullary collecting duct (mIMCD3) cell line, urea (200 mM) induced prompt (1-5 min) tyrosine phosphorylation of the EGF receptor. Pharmacological inhibition of EGF receptor kinase activity with AG1478 or PD153035 blocked urea-inducible transcription and expression of the immediate-early gene, Egr-1. AG1478 blocked, either fully or partially, other hallmarks of urea signalling including Elk-1 activation and extracellular signal-regulated kinase phosphorylation. EGF receptor kinase inhibition also blocked the cytoprotective effect of urea observed in the context of hypertonicity-inducible apoptosis. EGF receptor transactivation was likely to be attributable to metalloproteinase-dependent ectodomain shedding of an EGF receptor agonist because both specific and non-specific inhibitors of metalloproteinases blocked the urea effect. Heparin-binding EGF (HB-EGF), in particular, was implicated because the diphtheria toxin analogue and highly specific antagonist of HB-EGF, CRM197, also blocked urea-inducible transcription. In aggregate, these data indicate that signalling in response to urea in renal medullary cells requires EGF receptor transactivation, probably through autocrine action of HB-EGF.

Original languageEnglish (US)
Pages (from-to)479-487
Number of pages9
JournalBiochemical Journal
Volume370
Issue number2
DOIs
StatePublished - Mar 1 2003

Fingerprint

Genetic Transcription
Immediate-Early Genes
Transcription
Epidermal Growth Factor Receptor
Transcriptional Activation
Urea
Genes
Kidney
Metalloproteases
Epidermal Growth Factor
Phosphorylation
Heparin
Heparin Antagonists
Chemical activation
Diphtheria Toxin
Mitogen-Activated Protein Kinase 3
Extracellular Signal-Regulated MAP Kinases
Receptor Protein-Tyrosine Kinases
G-Protein-Coupled Receptors
Ducts

Keywords

  • Heparin-binding epidermal growth factor
  • Hypertonicity
  • Metalloproteinase

ASJC Scopus subject areas

  • Biochemistry

Cite this

Urea signalling to immediate-early gene transcription in renal medullary cells requires transactivation of the epidermal growth factor receptor. / Zhao, Hongyu; Tian, Wei; Xu, Hongshi; Cohen, David.

In: Biochemical Journal, Vol. 370, No. 2, 01.03.2003, p. 479-487.

Research output: Contribution to journalArticle

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