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KMID : 0043320150380020272
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Archives of Pharmacal Research
2015 Volume.38 No. 2 p.272 ~ p.281
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Involvement of Nrf2-GSH signaling in TGFβ1-stimulated epithelial-to-mesenchymal transition changes in rat renal tubular cells
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Ryoo In-Geun
Shin Dong-Ha
Kang Kyung-Shin
Kwak Mi-Kyoung
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Abstract
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Transforming growth factor-β1 (TGFβ1) induces epithelial-to-mesenchymal transition (EMT) in cultured renal tubular epithelial cells. This phenotypic transition has been known to be involved in the development of chronic kidney diseases by activating profibrotic gene expression. Since oxidative stress has been recognized as one of the contributors to this TGFβ1-mediated pathology, we investigated the potential involvement of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), which is a key transcription factor for the regulation of multiple antioxidant genes, in TGFβ1-stimulated EMT gene changes using the rat proximal tubular epithelial cell line NRK52E. The treatment of NRK52E with TGFβ1 led to changes in EMT gene expression, including increased α-Sma and decreased E-cadherin expression. In these cells, the TGFβ1 treatment decreased the transcript level of the catalytic subunit of γ-glutamate cysteine ligase (Gclc), a glutathione (GSH) biosynthetic enzyme, and reduced the total GSH content with a concomitant decrease in Nrf2 transcription activity. Accordantly, pre-incubation with the GSH precursor N-acetylcysteine attenuated TGFβ1-stimulated EMT gene changes. The involvement of Nrf2 in EMT gene changes has been demonstrated using NRK52E cells with nrf2 knockdown or pharmacological activation. When the expression of Nrf2 was stably silenced in NRK52E cells using interfering RNA administration, Gclc expression was significantly reduced and the increase in the levels of α-Sma and fibronectin-1 by TGFβ1 was greater than those in the nonspecific RNA control group. Conversely, Nrf2 activation and subsequent Gclc increase by Nrf2-activating sulforaphane alleviated the TGFβ1-stimulated α-Sma increase and E-cadherin decrease. Collectively, these results indicate that Nrf2-GSH signaling can modulate TGFβ1-stimulated EMT gene changes and further suggest a beneficial role of Nrf2 inducers in renal pathogenesis.
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KEYWORD
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TGFβ1, Epithelial-to-mesenchymal transition, Nrf2, GSH, Renal tubular cell
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