The NRF2-heme oxygenase-1 system modulates cyclosporin A-induced epithelial-mesenchymal transition and renal fibrosis

Dong Ha Shin, Hyun Min Park, Kyeong Ah Jung, Han Gon Choi, Jung Ae Kim, Dae Duk Kim, Sang Geon Kim, Keon Wook Kang, Sae Kwang Ku, Thomas W. Kensler, Mi Kyoung Kwak

Research output: Contribution to journalArticle

Abstract

Epithelial-mesenchymal transition (EMT) is an underlying mechanism of tissue fibrosis, generating myofibroblasts, which serve as the primary source of extracellular matrix production from tissue epithelial cells. Recently, EMT has been implicated in immunosuppressive cyclosporin A (CsA)-induced renal fibrosis. In this study, the potential role of NRF2, which is the master regulator of genes associated with the cellular antioxidant defense system, in CsA-induced EMT renal fibrosis has been investigated. Pretreatment of rat tubular epithelial NRK-52E cells with sulforaphane, an activator of NRF2, could prevent EMT gene changes such as the loss of E-cadherin and the increase in α-smooth muscle actin (α-SMA) expression. Conversely, genetic inhibition of NRF2 in these cells aggravated changes in CsA-induced EMT markers. These in vitro observations could be confirmed in vivo: CsA treatment resulted in severe renal damage and fibrosis with increased expression of α-SMA in NRF2-deficient mice compared to wild-type mice. NRF2-mediated amelioration of CsA-caused EMT changes could be accounted for in part by the regulation of heme oxygenase-1 (HO-1). CsA treatment increased HO-1 expression in an NRF2-dependent manner in NRK cells as well as in murine fibroblasts. Induction of HO-1 by CsA seems to be advantageous in that it counteracts EMT gene changes: specific increase in HO-1 expression caused by cobalt protoporphyrin prevented CsA-mediated α-SMA induction, whereas genetic inhibition of HO-1 by siRNA substantially enhanced α-SMA induction compared to control cells. Collectively, our results suggest that the NRF2-HO-1 system plays a protective role against CsA-induced renal fibrosis by modulating EMT gene changes.

Original languageEnglish (US)
Pages (from-to)1051-1063
Number of pages13
JournalFree Radical Biology and Medicine
Volume48
Issue number8
DOIs
StatePublished - Apr 1 2010

Keywords

  • Antioxidant defense system
  • Cyclosporin A
  • EMT
  • Free radicals
  • HO-1
  • NRF2
  • Oxidative stress
  • Renal fibrosis

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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  • Cite this

    Shin, D. H., Park, H. M., Jung, K. A., Choi, H. G., Kim, J. A., Kim, D. D., Kim, S. G., Kang, K. W., Ku, S. K., Kensler, T. W., & Kwak, M. K. (2010). The NRF2-heme oxygenase-1 system modulates cyclosporin A-induced epithelial-mesenchymal transition and renal fibrosis. Free Radical Biology and Medicine, 48(8), 1051-1063. https://doi.org/10.1016/j.freeradbiomed.2010.01.021