Urea and hypertonicity increase expression of heme oxygenase-1 in murine renal medullary cells

W. Tian, H. L. Bonkovsky, S. Shibahara, D. M. Cohen

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26 Scopus citations


Epithelial cells derived from the mammalian kidney medulla are responsive to urea at the levels of signal transduction and gene regulation. Hybridization of RNA harvested from control- and urea-treated murine inner medullary collecting duct (mIMCD3) cells with a cDNA expression array encoding stress-responsive genes suggested that heme oxygenase (HO)-1 mRNA was upregulated by urea. RNase protection assay confirmed this upregulation; hypertonicity also increased HO-1 mRNA expression but neither hypertonic NaCl nor urea were effective in the nonrenal 3T3 cell line. The effect on HO-1 expression appeared to be transcriptionally mediated on the basis of mRNA half-life studies and reporter gene analyses using the promoters of both human and chicken HO-1. Although urea signaling resembles that of heavy metal signaling in other contexts, the effect of urea on HO-1 transcription was independent of the cadmium response element in this promoter. Urea-inducible HO-1 expression was sensitive to antioxidants but not to scavengers of nitric oxide. Urea also upregulated HO-1 protein expression and pharmacological inhibition of HO-1 action with zinc protoporphyrin-sensitized mlMCD3 cells to the adverse effects of hypertonicity but not to urea. Coupled with the prior observation of others that HO-1 expression increases along the renal corticomedullary gradient, these data suggest that HO-1 expression may comprise an element of the adaptive response to hypertonicity and/or urea in renal epithelial cells.

Original languageEnglish (US)
Pages (from-to)F983-F991
JournalAmerican Journal of Physiology - Renal Physiology
Issue number5 50-5
StatePublished - 2001


  • Osmotic
  • Oxidative stress
  • Sodium chloride
  • Transcription

ASJC Scopus subject areas

  • Physiology
  • Urology


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