3H-1,2-dithiole-3-thione protects retinal pigment epithelium cells against Ultra-violet radiation via activation of Akt-mTORC1-dependent Nrf2-HO-1 signaling.
3H-1,2-dithiole-3-thione protects retinal pigment epithelium cells against Ultra-violet radiation via activation of Akt-mTORC1-dependent Nrf2-HO-1 signaling.
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3H-1,2-二硫醇-3-硫酮通过激活 Akt-mTORC1 依赖性 Nrf2-HO-1 信号传导保护视网膜色素上皮细胞免受紫外线辐射
DOI：
10.1038/srep25525
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发表时间：
2016-05-06
影响因子：
4.6
通讯作者：
Cao C
中科院分区：
文献类型：
--
作者：
Li KR;Yang SQ;Gong YQ;Yang H;Li XM;Zhao YX;Yao J;Jiang Q;Cao C
过量的紫外线辐射和活性氧（ROS）引起视网膜色素上皮（RPE）细胞损伤。nrf 2调节许多抗氧化基因的转录激活。在此，我们测试了3 H-1，2-二硫杂环戊烯-3-基（D3 T）在培养的RPE细胞（原代细胞和ARPE-19系）中对抗UV或ROS损伤的潜在作用。我们发现，D3 T显着抑制UV-/H2 O2诱导的RPE细胞死亡和凋亡。D3 T预处理显著抑制了UV刺激的ROS产生。在培养的RPE细胞中，D3 T诱导Nrf 2磷酸化，导致Nrf 2与KEAP 1解离并随后在核中积聚。这导致抗氧化反应元件（ARE）依赖性基因血红素加氧酶-1（HO-1）的表达。D3 T介导的细胞保护作用需要Nrf 2-HO-1激活。Nrf 2 shRNA敲除或S40 T显性失活突变以及HO-1抑制剂锌原卟啉（ZnPP）在很大程度上抑制了D3 T对UV辐射的RPE细胞保护作用。然而，外源性过表达Nrf 2增强了RPE细胞中D3 T的活性。进一步的研究表明D3 T可激活培养的RPE细胞中的Akt/mTORC 1。Akt-mTORC 1抑制剂或Akt 1基因敲低的shRNA不仅抑制D3 T诱导的Nrf 2-HO-1激活，而且消除了RPE细胞保护作用。在体内，D3 T玻璃体内注射保护小鼠免受光诱导的视网膜功能障碍。因此，D3 T通过激活Akt-mTORC 1-Nrf 2-HO-1信号轴保护RPE细胞免受UV诱导的损伤。
Excessive UV radiation and reactive oxygen species (ROS) cause retinal pigment epithelium (RPE) cell injuries. Nrf2 regulates transcriptional activation of many anti-oxidant genes. Here, we tested the potential role of 3H-1,2-dithiole-3-thione (D3T) against UV or ROS damages in cultured RPE cells (both primary cells and ARPE-19 line). We showed that D3T significantly inhibited UV-/H2O2-induced RPE cell death and apoptosis. UV-stimulated ROS production was dramatically inhibited by D3T pretreatment. D3T induced Nrf2 phosphorylation in cultured RPE cells, causing Nrf2 disassociation with KEAP1 and its subsequent nuclear accumulation. This led to expression of antioxidant response elements (ARE)-dependent gene heme oxygenase-1 (HO-1). Nrf2-HO-1 activation was required for D3T-mediated cytoprotective effect. Nrf2 shRNA knockdown or S40T dominant negative mutation as well as the HO-1 inhibitor Zinc protoporphyrin (ZnPP) largely inhibited D3T’s RPE cytoprotective effects against UV radiation. Yet, exogenous overexpression Nrf2 enhanced D3T’s activity in RPE cells. Further studies showed that D3T activated Akt/mTORC1 in cultured RPE cells. Akt-mTORC1 inhibitors, or Akt1 knockdown by shRNA, not only inhibited D3T-induced Nrf2-HO-1 activation, but also abolished the RPE cytoprotective effects. In vivo, D3T intravitreal injection protected from light-induced retinal dysfunctions in mice. Thus, D3T protects RPE cells from UV-induced damages via activation of Akt-mTORC1-Nrf2-HO-1 signaling axis.