An internal enhancer regulates heme- and cadmium-mediated induction of human heme oxygenase-1

Nathalie Hill-Kapturczak, Eric Sikorski, Christy Voakes, Jairo Garcia, Harry S. Nick, Anupam Agarwal

Research output: Contribution to journalArticlepeer-review

67 Scopus citations

Abstract

Heme oxygenase-1 (HO-1) catalyzes the rate-limiting step in heme degradation, releasing iron, carbon monoxide, and biliverdin. Induction of HO-1 is an adaptive and beneficial response in renal and nonrenal settings of tissue injury. The purpose of this study was to characterize the regulation of the human HO-1 gene in renal proximal tubule and aortic endothelial cells in response to heme and cadmium. Evaluation of multiple human HO-1 promoter-reporter constructs up to -9.1 kb demonstrated only a partial response to heme and cadmium. In an effort to mimic endogenous stimulus-dependent levels of HO-1 induction, we evaluated the entire 12.5 kb of the human HO-1 gene, including introns and exons, in conjunction with a -4.5-kb human HO-1 promoter and observed significant heme- and cadmium-mediated induction of the reporter gene, suggesting the presence of an internal enhancer. Enhancer function was orientation independent and required a region between -3.5 and -4.5 kb of the human HO-1 promoter. Our studies identified a novel enhancer internal to the human HO-1 gene that, in conjunction with the HO-1 promoter, recapitulates heme- and cadmium-mediated induction of the endogenous HO-1 gene. Elucidation of the molecular regulation of the human HO-1 gene will allow for the development of therapeutic strategies to manipulate HO-1 gene expression in pathological states.

Original languageEnglish (US)
Pages (from-to)F515-F523
JournalAmerican Journal of Physiology - Renal Physiology
Volume285
Issue number3 54-3
DOIs
StatePublished - Sep 1 2003

Keywords

  • Endothelial cells
  • Gene transcription
  • Heme proteins
  • Molecular regulation
  • Renal proximal tubule cells

ASJC Scopus subject areas

  • Physiology
  • Urology

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