Retinoic acid increases hypoxia-inducible factor-1伪 through intracrine prostaglandin E₂ signaling in human renal proximal tubular cells HK-2

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• 作者：Ana B. Ferná ; ndez-Martí ; nez^a ; ^{anab.fernandez@uah.es} ; Marí ; a I. Arenas Jimé ; nez^b ; Francisco J. Lucio Cazañ ; a^a
• 关键词：Hypoxia inducible factor-1伪 ; All trans retinoic acid ; Cyclooxigenases ; Prostaglandin E2 ; Human proximal tubular cells
• 刊名：Biochimica et Biophysica Acta (BBA)/Molecular and Cell Biology of Lipids
• 出版年：2012
• 期刊代码：18_13881981
• 类别：bio
• 出版时间：April, 2012
• 卷：1821
• 期：4
• 页码：672-683
• 文件大小：11734 K

摘要

We have previously shown in HK-2 cells that ATRA (all-trans-retinoic acid) up-regulates HIF-1伪 (hypoxia-inducible factor-1伪) in normoxia, which results in increased production of renal protector VEGF-A (vascular endothelial growth factor-A). Here we investigated the role of COXs (cyclooxygenases) in these effects and we found that, i) ATRA increased the expression of COX-1 and COX-2 mRNA and protein and the intracellular levels (but not the extracellular ones) of PGE₂. Furthermore, inhibitors of COX isoenzymes blocked ATRA-induced increase in intracellular PGE₂, HIF-1伪 up-regulation and increased VEGF-A production. Immunofluorescence analysis found intracellular staining for EP1-4 receptors (PGE₂ receptors). These results indicated that COX activity is critical for ATRA-induced HIF-1伪 up-regulation and suggested that intracellular PGE₂ could mediate the effects of ATRA; ii) Treatment with PGE₂ analog 16,16-dimethyl-PGE₂ resulted in up-regulation of HIF-1伪 and antagonists of EP1-4 receptors inhibited 16,16-dimethyl-PGE₂- and ATRA-induced HIF-1伪 up-regulation. These results confirmed that PGE₂ mediates the effects of ATRA on HIF-1伪 expression; iii) Prostaglandin uptake transporter inhibitor bromocresol green blocked the increase in HIF-1伪 expression induced by PGE₂ or by PGE₂-increasing cytokine interleukin-1尾, but not by ATRA. Therefore only intracellular PGE₂ is able to increase HIF-1伪 expression. In conclusion, intracellular PGE₂ increases HIF-1伪 expression and mediates ATRA-induced HIF-1伪 up-regulation.