Hypoxia-inducible factor prolyl-hydroxylase-2 mediates transforming growth factor beta 1-induced epithelial-mesenchymal transition in renal tubular cells.
Hypoxia-inducible factor prolyl-hydroxylase-2 mediates transforming growth factor beta 1-induced epithelial-mesenchymal transition in renal tubular cells.
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DOI：
10.1016/j.bbamcr.2013.02.029
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发表时间：
2013-06
影响因子：
5.1
通讯作者：
Li, Ningjun
中科院分区：
文献类型：
--
作者：
Han, Wei-Qing;Zhu, Qing;Hu, Junping;Li, Pin-Lan;Zhang, Fan;Li, Ningjun
转化生长因子β 1（TGF-β1）诱导的肾上皮细胞间质转化（EMT）在慢性肾脏病肾小管间质纤维化中起关键作用。由于低氧诱导因子（HIF）-1α介导TGF-β1诱导的信号通路，我们利用体外培养的肾小管细胞验证了HIF-1α及其上游调节因子脯氨酰羟化酶结构域蛋白（PHDs）参与TGF-β1诱导的EMT的假说。我们的结果表明，TGF-β1刺激了肾小管细胞的EMT，表现为上皮标志物P-钙粘蛋白的显着减少，间充质标志物α-平滑肌肌动蛋白（α-SMA）和成纤维细胞特异性蛋白1（FSP-1）的增加。同时发现TGF-β1可时间依赖性地增加HIF-1α的表达，HIF-1α siRNA可显著抑制TGF-β1诱导的EMT，提示HIF-1α介导TGF-β1诱导的EMT。实时荧光定量PCR检测结果表明，PHD 1和PHD 2的检出率为0.21：1.0，而PHD 3的检出率为0.21：1.0。重要的是，TGF-β1降低了PHD 2 mRNA和蛋白质，但不降低PHD 1。此外，PHD 2转基因的过表达几乎完全阻止了TGF-β1诱导的HIF-1α积累和EMT标志物的变化，表明PHD 2参与了TGF-β1诱导的EMT。Smad 2/3抑制剂SB 431542可阻断TGF-β1诱导的PHD 2减少，提示Smad 2/3可能通过PHD 2/HIF-1α途径介导TGF-β1诱导的EMT。结论TGF-β1通过Smad依赖的信号通路降低PHD 2表达，从而导致HIF-1α在肾小管细胞内积聚，进而导致EMT。本研究提示PHD 2/HIF-1α是一条新的信号通路，介导TGF-β1的致纤维化作用，可能成为慢性肾脏病治疗的新靶点。
Transforming growth factor beta 1 (TGF-β1)-induced epithelial-mesenchymal transition (EMT) in kidney epithelial cells plays a key role in renal tubulointerstitial fibrosis in chronic kidney diseases. As hypoxia-inducible factor (HIF)-1α is found to mediate TGF-β1-induced signaling pathway, we tested the hypothesis that HIF-1α and its upstream regulator prolyl hydroxylase domain-containing proteins (PHDs) are involved in TGF-β1-induced EMT using cultured renal tubular cells. Our results showed that TGF-β1 stimulated EMT in renal tubular cells as indicated by the significant decrease in epithelial marker P-cadherin, and the increase in mesenchymal markers α-smooth muscle actin (α-SMA) and fibroblast-specific protein 1 (FSP-1). Meanwhile, we found that TGF-β1 time-dependently increased HIF-1α and that HIF-1α siRNA significantly inhibited TGF-β1-induced EMT, suggesting that HIF-1α mediated TGF-β1 induced-EMT. Real-time PCR showed that PHD1 and PHD2, rather than PHD3, could be detected, with PHD2 as the predominant form of PHDs (PHD1:PHD2 = 0.21:1.0). Importantly, PHD2 mRNA and protein, but not PHD1, was decreased by TGF-β1. Furthermore, over-expression of PHD2 transgene almost fully prevented TGF-β1-induced HIF-1α accumulation and EMT marker changes, indicating that PHD2 is involved in TGF-β1-induced EMT. Finally, Smad2/3 inhibitor SB431542 prevented TGF-β1-induced PHD2 decrease, suggesting that Smad2/3 may mediate TGF-β1-induced EMT through PHD2/HIF-1α pathway. It is concluded that TGF-β1 decreased PHD2 expression via a Smad-dependent signaling pathway, thereby leading to HIF-1α accumulation and then EMT in renal tubular cells. The present study suggests that PHD2/HIF-1α is a novel signaling pathway mediating the fibrogenic effect of TGF-β1, and may be a new therapeutic target in chronic kidney diseases.
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影响因子：
56.9
作者：
Jaakkola, P;Mole, DR;Ratcliffe, PJ
通讯作者：
Ratcliffe, PJ
影响因子：
8
作者：
Chae, K. S.;Kang, M. J.;Chi, S. G.
通讯作者：
Chi, S. G.
DOI：
10.1152/ajprenal.90500.2008
发表时间：
2009-03-01
影响因子：
4.2
作者：
Hills, Claire E.;Al-Rasheed, Nawal;Brunskill, Nigel J.
通讯作者：
Brunskill, Nigel J.
DOI：
10.1164/rccm.201106-0965oc
发表时间：
2012-03-01
影响因子：
24.7
作者：
MacKinnon, Alison C.;Gibbons, Michael A.;Sethi, Tariq
通讯作者：
Sethi, Tariq
影响因子：
13.6
作者：
Burns, Wendy C.;Twigg, Stephen M.;Kantharidis, Phillip
通讯作者：
Kantharidis, Phillip