Hypoxia-inducible factor prolyl-hydroxylase-2 mediates transforming growth factor beta 1-induced epithelial-mesenchymal transition in renal tubular cells

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• 作者：Wei-Qing Han^a ; ^b ; Qing Zhu^a ; Junping Hu^a ; Pin-Lan Li^a ; Fan Zhang^a ; Ningjun Li^a ; ^nli@vcu.edu
• 关键词：¦Á-SMA ; ¦Á-smooth muscle actin ; EMT ; epithelial-to-mesenchymal transition ; FSP-1 ; fibroblast-specific protein 1 ; HIF-1¦Á ; hypoxia-inducible factor 1¦Á ; PHD ; prolyl hydroxylase domain ; TFIID ; transcription factor II D ; TGF-¦Â1 ; transforming growth factor b
• 刊名：Biochimica et Biophysica Acta (BBA)/Molecular Cell Research
• 出版年：2013
• 出版时间：June, 2013
• 年：2013
• 卷：1833
• 期：6
• 页码：1454-1462
• 全文大小：1257 K

文摘

Transforming growth factor beta 1 (TGF-¦Â1)-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)-1¦Á is found to mediate TGF-¦Â1-induced signaling pathway, we tested the hypothesis that HIF-1¦Á and its upstream regulator prolyl hydroxylase domain-containing proteins (PHDs) are involved in TGF-¦Â1-induced EMT using cultured renal tubular cells. Our results showed that TGF-¦Â1 stimulated EMT in renal tubular cells as indicated by the significant decrease in epithelial marker P-cadherin, and the increase in mesenchymal markers ¦Á-smooth muscle actin (¦Á-SMA) and fibroblast-specific protein 1 (FSP-1). Meanwhile, we found that TGF-¦Â1 time-dependently increased HIF-1¦Á and that HIF-1¦Á siRNA significantly inhibited TGF-¦Â1-induced EMT, suggesting that HIF-1¦Á mediated TGF-¦Â1 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, were decreased by TGF-¦Â1. Furthermore, over-expression of PHD2 transgene almost fully prevented TGF-¦Â1-induced HIF-1¦Á accumulation and EMT marker changes, indicating that PHD2 is involved in TGF-¦Â1-induced EMT. Finally, Smad2/3 inhibitor SB431542 prevented TGF-¦Â1-induced PHD2 decrease, suggesting that Smad2/3 may mediate TGF-¦Â1-induced EMT through PHD2/HIF-1¦Á pathway. It is concluded that TGF-¦Â1 decreased PHD2 expression via an Smad-dependent signaling pathway, thereby leading to HIF-1¦Á accumulation and then EMT in renal tubular cells. The present study suggests that PHD2/HIF-1¦Á is a novel signaling pathway mediating the fibrogenic effect of TGF-¦Â1, and may be a new therapeutic target in chronic kidney diseases.