The NRF2-heme oxygenase-1 system modulates cyclosporin A-induced epithelial-mesenchymal transition and renal fibrosis.
The NRF2-heme oxygenase-1 system modulates cyclosporin A-induced epithelial-mesenchymal transition and renal fibrosis.
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DOI：
10.1016/j.freeradbiomed.2010.01.021
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发表时间：
2010-04-15
影响因子：
7.4
通讯作者：
Kwak, Mi-Kyoung
中科院分区：
文献类型：
--
作者：
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
上皮-间质转化（epithelial -mesenchymal transition， EMT）是组织纤维化的一种潜在机制，通过产生肌成纤维细胞，肌成纤维细胞是组织上皮细胞产生细胞外基质的主要来源。最近，有研究表明EMT与免疫抑制性环孢素A （CsA）诱导的肾纤维化有关。在本研究中，研究人员研究了NRF2在csa诱导的emt -肾纤维化中的潜在作用。NRF2是与细胞抗氧化防御系统相关的基因的主要调节因子。用NRF2激活剂萝卜硫素预处理大鼠小管上皮NRK-52E细胞，可以防止EMT基因的变化，如E-cadherin的丢失和α-平滑肌肌动蛋白（α-SMA）表达的增加。相反，NRF2在这些细胞中的遗传抑制加重了csa诱导的EMT标记物的变化。这些体外观察结果在体内也得到了证实：与野生型小鼠相比，csa治疗后nrf2缺陷小鼠的α-SMA表达增加，出现了严重的肾损伤和纤维化。nrf2介导的CsA-EMT变化的改善可能部分归因于血红素加氧酶-1 （HO-1）的调节。CsA处理在NRK细胞和小鼠成纤维细胞中以nrf2依赖的方式增加HO-1的表达。CsA通过抵消EMT基因的改变诱导HO-1似乎是有利的：钴原卟啉特异性增加HO-1的表达，阻止了CsA介导的α-SMA诱导，而siRNA对HO-1的遗传抑制，与对照细胞相比，显著增强了α-SMA诱导。总的来说，我们目前的结果表明NRF2-HO-1系统通过调节EMT基因的变化对csa诱导的肾纤维化起保护作用。
Epithelial-mesenchymal transition (EMT) is an underlying mechanism of tissue fibrosis by generating myofibroblasts, which serve as the primary source of extracellular matrix production from tissue epithelial cells. Recently, it has been suggested that EMT is implicated in immunosuppressive cyclosporine A (CsA)-induced renal fibrosis. In the present 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. Pre-treatment 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 of 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 developed 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-EMT changes could be accounted 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 murine fibroblasts. Induction of HO-1 by CsA appears to be advantageous by counteracting EMT gene changes: specific increase of HO-1 expression by cobalt protoporphyrin prevented CsA-mediated α-SMA induction, while genetic inhibition of HO-1 by siRNA substantially enhanced α-SMA induction compared to control cells. Collectively, our current results suggest that the NRF2-HO-1 system plays a protective role against CsA-induced renal fibrosis by modulating EMT gene changes.
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DOI：
10.1111/j.1600-6143.2008.02463.x
发表时间：
2009-01
期刊：
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
影响因子：
--
作者：
Djamali A;Vidyasagar A;Adulla M;Hullett D;Reese S
通讯作者：
Reese S
影响因子：
2.9
作者：
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通讯作者：
GRIFFITH, OW
影响因子：
5.2
作者：
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通讯作者：
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DOI：
10.1006/bbrc.1997.6943
发表时间：
1997-07-18
影响因子：
3.1
作者：
Itoh, K;Chiba, T;Nabeshima, Y
通讯作者：
Nabeshima, Y
影响因子：
3.8
作者：
Choi, Hoo-Kyun;Pokharel, Yuba Raj;Kang, Keon Wook
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