Involvement of Nrf2-GSH signaling in TGFβ1-stimulated epithelial-to-mesenchymal transition changes in rat renal tubular cells

被引:39
作者
Ryoo, In-geun [1 ]
Shin, Dong-ha [2 ]
Kang, Kyung-Shin [3 ]
Kwak, Mi-Kyoung [1 ]
机构
[1] Catholic Univ Korea, Coll Pharm, Puchon 420743, Gyeonggi Do, South Korea
[2] Yeungnam Univ, Coll Pharm, Kyongsan 712749, South Korea
[3] Daewon Foreign Language High Sch, Seoul 143713, South Korea
基金
新加坡国家研究基金会;
关键词
TGF beta 1; Epithelial-to-mesenchymal transition; Nrf2; GSH; Renal tubular cell; UNILATERAL URETERAL OBSTRUCTION; IDIOPATHIC PULMONARY-FIBROSIS; TGF-BETA; OXIDATIVE STRESS; MOLECULAR-MECHANISMS; DIABETIC-NEPHROPATHY; TUBULOINTERSTITIAL FIBROSIS; NRF2-KEAP1; PATHWAY; HEME OXYGENASE-1; GENE-EXPRESSION;
D O I
10.1007/s12272-014-0380-y
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Transforming growth factor-beta 1 (TGF beta 1) 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 TGF beta 1-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 TGF beta 1-stimulated EMT gene changes using the rat proximal tubular epithelial cell line NRK52E. The treatment of NRK52E with TGF beta 1 led to changes in EMT gene expression, including increased alpha-Sma and decreased E-cadherin expression. In these cells, the TGF beta 1 treatment decreased the transcript level of the catalytic subunit of gamma-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 TGF beta 1-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 alpha-Sma and fibronectin-1 by TGF beta 1 was greater than those in the nonspecific RNA control group. Conversely, Nrf2 activation and subsequent Gclc increase by Nrf2-activating sulforaphane alleviated the TGF beta 1-stimulated alpha-Sma increase and E-cadherin decrease. Collectively, these results indicate that Nrf2-GSH signaling can modulate TGF beta 1-stimulated EMT gene changes and further suggest a beneficial role of Nrf2 inducers in renal pathogenesis.
引用
收藏
页码:272 / 281
页数:10
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