Premium
Role of NRF2 in cyclosporine A‐induced renal fibrosis
Author(s) -
Jung KyeongAh,
Shin Dongha,
Lee Sanghwan,
Kensler Thomas W.,
Kwak MiKyoung
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.968.4
Subject(s) - myofibroblast , epithelial–mesenchymal transition , fibrosis , cancer research , extracellular matrix , chemistry , vimentin , biology , microbiology and biotechnology , downregulation and upregulation , immunology , gene , medicine , biochemistry , immunohistochemistry
Epithelial‐mesenchymal transition (EMT) is an underlying mechanism of tissue fibrosis by generating myofibroblasts, which serve as the primary source of extracellular matrix production, from tissue epithelial cells. In the present study, the potential role of NRF2, which is the master regulator of genes associated with the cellular antioxidant defense system, in cyclosporine A (CsA)‐induced EMT‐fibrosis has been investigated. Pre‐treatment 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 of 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 developed 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‐EMT changes could be accounted in part by the regulation of heme oxygenase‐1 (HO‐1). Induction of HO‐1 by CsA appears to be advantageous by counteracting EMT gene changes: specific increase of HO‐1 expression by CoPP prevented CsA‐mediated α‐SMA induction, while genetic inhibition of HO‐1 by siRNA administration substantially enhanced α‐SMA induction compared to control cells. Collectively, our current results suggest that the NRF2 system, particularly its target gene HO‐1, plays a protective role against CsA‐induced renal fibrosis by modulating EMT changes.