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 language | English (US) |
|---|---|
| Pages (from-to) | 1051-1063 |
| Number of pages | 13 |
| Journal | Free Radical Biology and Medicine |
| Volume | 48 |
| Issue number | 8 |
| DOIs | |
| State | Published - Apr 2010 |
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Keywords
- Antioxidant defense system
- Cyclosporin A
- EMT
- Free radicals
- HO-1
- NRF2
- Oxidative stress
- Renal fibrosis
ASJC Scopus subject areas
- Biochemistry
- Physiology (medical)
Cite this
The NRF2-heme oxygenase-1 system modulates cyclosporin A-induced epithelial-mesenchymal transition and renal fibrosis. / Shin, Dong Ha; Park, Hyun Min; Jung, Kyeong Ah; Choi, Han Gon; Kim, Jung Ae; Kim, Dae Duk; Kim, Sang Geon; Kang, Keon Wook; Ku, Sae Kwang; Kensler, Thomas W; Kwak, Mi Kyoung.
In: Free Radical Biology and Medicine, Vol. 48, No. 8, 04.2010, p. 1051-1063.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - The NRF2-heme oxygenase-1 system modulates cyclosporin A-induced epithelial-mesenchymal transition and renal fibrosis
AU - Shin, Dong Ha
AU - Park, Hyun Min
AU - Jung, Kyeong Ah
AU - Choi, Han Gon
AU - Kim, Jung Ae
AU - Kim, Dae Duk
AU - Kim, Sang Geon
AU - Kang, Keon Wook
AU - Ku, Sae Kwang
AU - Kensler, Thomas W
AU - Kwak, Mi Kyoung
PY - 2010/4
Y1 - 2010/4
N2 - 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.
AB - 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.
KW - Antioxidant defense system
KW - Cyclosporin A
KW - EMT
KW - Free radicals
KW - HO-1
KW - NRF2
KW - Oxidative stress
KW - Renal fibrosis
UR - http://www.scopus.com/inward/record.url?scp=77950517594&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77950517594&partnerID=8YFLogxK
U2 - 10.1016/j.freeradbiomed.2010.01.021
DO - 10.1016/j.freeradbiomed.2010.01.021
M3 - Article
C2 - 20096777
AN - SCOPUS:77950517594
VL - 48
SP - 1051
EP - 1063
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
SN - 0891-5849
IS - 8
ER -