Suppression of Nrf2 signaling by angiotensin II in murine renal epithelial cells

Arch Pharm Res. 2011 May;34(5):829-36. doi: 10.1007/s12272-011-0517-1. Epub 2011 Jun 9.

Abstract

Angiotensin II (ATII), a physiologically active mediator of the renin-angiotensin system, has been shown to be associated with renal fibrosis pathophysiology. In our current study with murine renal epithelial TCMK-1 cells, ATII inhibited the expression of NF-E2-related factor 2 (Nrf2)-target antioxidant genes such as NAD(P)H: quinone oxidoreductase-1 and γ-glutamate cysteine ligase (GCL). In accord to the reduced expression of GCL, a GSH biosynthesis enzyme, ATII treatment reduced intracellular GSH content and increased the levels of reactive oxygen species (ROS). While, there was no significant changes in nuclear protein levels of Nrf2 following ATII treatment, implying the potential alterations in the expression of partner proteins of Nrf2. Our measurement of Nrf2 partner bZIP transcription factors, including Bach1, small Maf proteins, and activating transcription factor 3 (ATF3) showed that the expression level for ATF3 was enhanced in ATII-treated TCMK cells. Presumably through ATII-induced oxidative stress, ATII treatment was found to enhance the inducible level of TGFβ-mediated α-smooth muscle actin (α-SMA) expression, which is one of molecular markers of renal fibrosis. In conclusion, our results indicate that ATII suppresses Nrf2-GSH signaling in murine renal epithelial cells. Elevated ROS levels in ATII exposed epithelial cells might be a causing factor contributing to renal fibrosis pathology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Angiotensin II / metabolism*
  • Animals
  • Basic-Leucine Zipper Transcription Factors / genetics
  • Basic-Leucine Zipper Transcription Factors / metabolism
  • Biomarkers / metabolism
  • Cell Line
  • Cell Nucleus / metabolism
  • Epithelial Cells / metabolism*
  • Epithelial-Mesenchymal Transition
  • Fibrosis
  • Gene Expression Regulation*
  • Glutamate-Cysteine Ligase / genetics
  • Glutamate-Cysteine Ligase / metabolism
  • Glutathione / metabolism
  • Kidney / metabolism*
  • Kidney / pathology
  • Mice
  • NAD(P)H Dehydrogenase (Quinone) / genetics
  • NAD(P)H Dehydrogenase (Quinone) / metabolism
  • NF-E2-Related Factor 2 / antagonists & inhibitors*
  • NF-E2-Related Factor 2 / metabolism
  • Oxidation-Reduction
  • Oxidative Stress
  • RNA, Messenger / metabolism
  • Reactive Oxygen Species / metabolism
  • Signal Transduction*
  • Transforming Growth Factor beta / metabolism

Substances

  • Acta2 protein, mouse
  • Actins
  • Basic-Leucine Zipper Transcription Factors
  • Biomarkers
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • RNA, Messenger
  • Reactive Oxygen Species
  • Transforming Growth Factor beta
  • Angiotensin II
  • NAD(P)H Dehydrogenase (Quinone)
  • Nqo1 protein, mouse
  • Glutamate-Cysteine Ligase
  • Glutathione