Urea-associated oxidative stress and Gadd153/CHOP induction

Am J Physiol. 1999 May;276(5):F786-93. doi: 10.1152/ajprenal.1999.276.5.F786.

Abstract

Urea treatment (100-300 mM) increased expression of the oxidative stress-responsive transcription factor, Gadd153/CHOP, at the mRNA and protein levels (at >/=4 h) in renal medullary mIMCD3 cells in culture, whereas other solutes did not. Expression of the related protein, CCAAT/enhancer-binding protein (C/EBP-beta), was not affected, nor was expression of the sensor of endoplasmic reticulum stress, grp78. Urea modestly increased Gadd153 transcription by reporter gene analysis but failed to influence Gadd153 mRNA stability. Importantly, upregulation of Gadd153 mRNA and protein expression by urea was antioxidant sensitive. Accordingly, urea treatment was associated with oxidative stress, as quantitated by intracellular reduced glutathione content in mIMCD3 cells. In addition, antioxidant treatment partially inhibited the ability of urea to activate transcription of an Egr-1 luciferase reporter gene. Therefore oxidative stress represents a novel solute-signaling pathway in the kidney medulla and, potentially, in other tissues.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antioxidants / pharmacology
  • Blotting, Northern
  • CCAAT-Enhancer-Binding Proteins
  • Cadmium Chloride / pharmacology
  • Cells, Cultured
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / physiology
  • Early Growth Response Protein 1
  • Gene Expression / drug effects
  • Gene Expression / physiology
  • Hypertonic Solutions / pharmacology
  • Immediate-Early Proteins*
  • Kidney Medulla / cytology
  • Kidney Tubules, Collecting / cytology
  • Mice
  • Nuclear Proteins / genetics
  • Oxidative Stress / drug effects
  • Oxidative Stress / genetics*
  • RNA, Messenger / metabolism
  • Sodium Chloride / pharmacology
  • Transcription Factor CHOP
  • Transcription Factors / genetics*
  • Transcription Factors / physiology
  • Transcription, Genetic / physiology
  • Urea / pharmacology*
  • Uremia / metabolism
  • Water-Electrolyte Balance / physiology

Substances

  • Antioxidants
  • CCAAT-Enhancer-Binding Proteins
  • DNA-Binding Proteins
  • Ddit3 protein, mouse
  • Early Growth Response Protein 1
  • Egr1 protein, mouse
  • Hypertonic Solutions
  • Immediate-Early Proteins
  • Nuclear Proteins
  • RNA, Messenger
  • Transcription Factors
  • Transcription Factor CHOP
  • Sodium Chloride
  • Urea
  • Cadmium Chloride