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

doi:10.1016/j.freeradbiomed.2010.01.021

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

Bloomberg School of Public Health

Research output: Contribution to journal › Article › peer-review

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	https://doi.org/10.1016/j.freeradbiomed.2010.01.021
State	Published - Apr 2010

Keywords

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

ASJC Scopus subject areas

Biochemistry
Physiology (medical)

Access to Document

10.1016/j.freeradbiomed.2010.01.021

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

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 › peer-review

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. / The NRF2-heme oxygenase-1 system modulates cyclosporin A-induced epithelial-mesenchymal transition and renal fibrosis. In: Free Radical Biology and Medicine. 2010 ; Vol. 48, No. 8. pp. 1051-1063.

@article{58751959843548acab76af571c812052,

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

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.",

keywords = "Antioxidant defense system, Cyclosporin A, EMT, Free radicals, HO-1, NRF2, Oxidative stress, Renal fibrosis",

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

note = "Funding Information: We thank Patrick M. Dolan (Johns Hopkins University, Baltimore, MD, USA) for maintaining and genotyping the mice. This work was supported by a National Research Foundation of Korea grant, funded by the Korean government (2009-0066689), to M.-K. Kwak and by NIH Grant CA94076 to T.W. Kensler. ",

year = "2010",

month = apr,

doi = "10.1016/j.freeradbiomed.2010.01.021",

language = "English (US)",

volume = "48",

pages = "1051--1063",

journal = "Free Radical Biology and Medicine",

issn = "0891-5849",

publisher = "Elsevier Inc.",

number = "8",

}

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

N1 - Funding Information: We thank Patrick M. Dolan (Johns Hopkins University, Baltimore, MD, USA) for maintaining and genotyping the mice. This work was supported by a National Research Foundation of Korea grant, funded by the Korean government (2009-0066689), to M.-K. Kwak and by NIH Grant CA94076 to T.W. Kensler.

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 -

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

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this