Partial contribution of the Keap1-Nrf2 system to cadmium-mediated metallothionein expression in vascular endothelial cells

Yasuhiro Shinkai, Tomoki Kimura, Ayaka Itagaki, Chika Yamamoto, Keiko Taguchi, Masayuki Yamamoto, Yoshito Kumagai, Toshiyuki Kaji

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Cadmium is an environmental electrophile that modifies protein reactive thiols such as Kelch-like ECH-associated protein 1 (Keap1), a negative regulator of nuclear factor-erythroid 2-related factor 2 (Nrf2). In the present study, we investigated a role of the Keap1-Nrf2 system in cellular response to cadmium in vascular endothelial cells. Exposure of bovine aortic endothelial cells to cadmium resulted in modification of Keap1 and Nrf2 activation, thereby up-regulating not only its typical downstream proteins but also metallothionein-1/2. Experiments with siRNA-mediated knockdown of Nrf2 or Keap1 supported participation of the Keap1-Nrf2 system in the modulation of metallothionein-1/2 expression. Furthermore, chromatin immunoprecipitation assay showed that Nrf2 was recruited to the antioxidant response element of the promoter region of the bovine metallothionein-gene in the presence of cadmium. These results suggest that the transcription factor Nrf2 plays, at least in part, a role in the changes in metallothionein expression mediated by exposure to cadmium.

Original languageEnglish
Pages (from-to)37-46
Number of pages10
JournalToxicology and Applied Pharmacology
Volume295
DOIs
Publication statusPublished - 2016 Mar 15

Keywords

  • Antioxidant response element
  • Cadmium
  • Keap1
  • Metallothionein
  • Nrf2

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

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