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

Title
The NRF2-heme oxygenase-1 system modulates cyclosporin A-induced epithelial-mesenchymal transition and renal fibrosis
Author(s)
곽미경신동하[신동하]박현민[박현민]정경아[정경아]최한곤김정애김상건[김상건]김대덕[김대덕]강건욱[강건욱]구세광[구세광]Thomas W. Kensler[Thomas W. Kensler]
Keywords
IDIOPATHIC PULMONARY-FIBROSIS; MOLECULAR-MECHANISMS; ANTIOXIDANT RESPONSE; URETERAL OBSTRUCTION; HEME OXYGENASE; LIVER-INJURY; RAT-KIDNEY; PATHWAY; CELLS; PROTECTS
Issue Date
201004
Publisher
ELSEVIER SCIENCE INC
Citation
FREE RADICAL BIOLOGY AND MEDICINE, v.48, no.8, pp.1051 - 1063
Abstract
Epithelial-mesenchymal transition (EMT) is an underlying mechanism of tissue (Thins's, generating myofibroblasts, which serve as the primary source of extracellular matrix production from tissue epithelial cells Recently, EMT has been implicated in immunosuppressive cyclospotin 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 at 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 a-smooth muscle actin (alpha-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 sever e renal damage and fibrosis with increased expression of a-SMA in NRf2-deficient mice compared to wild-type mice NM-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-I by CsA seems to be advantageous in that it counteracts EMT gene changes specific increase in HO-1 expression caused by cobalt protoporphyrm prevented CsA-mediated a-SMA induction, whereas genetic inhibition of HO-1 by siRNA substantially enhanced a-SMA induction compared to control cells Collectively, out results suggest that the NRF2-HO-1 system plays a protective role against CsA-induced renal fibrosis by modulating EMT gene changes (C) 2010 Elsevier Inc All lights reserved
URI
http://hdl.handle.net/YU.REPOSITORY/22633http://dx.doi.org/10.1016/j.freeradbiomed.2010.01.021
ISSN
0891-5849
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약학대학 > 약학부 > Articles
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