Departamento de Fisiología, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain.
Int J Biochem Cell Biol. 2012 Dec;44(12):2185-93. doi: 10.1016/j.biocel.2012.08.015. Epub 2012 Aug 30.
We have previously found in human renal proximal tubular HK-2 cells that hypoxia- and all-trans retinoic acid-induced hypoxia-inducible factor-1α up-regulation is accompanied by retinoic acid receptor-β up-regulation. Here we first investigated whether hypoxia-inducible factor-1α expression is dependent on retinoic acid receptor-β and our results confirmed it since (i) hypoxia-inducible factor-1α-inducing agents hypoxia, hypoxia-mimetic agent desferrioxamine, all-trans retinoic acid and interleukin-1β increased retinoic acid receptor-β expression, (ii) hypoxia-inducible factor-1α up-regulation was prevented by retinoic acid receptor-β antagonist LE-135 or siRNA retinoic acid receptor-β and (iii) there was direct binding of retinoic acid receptor-β to the retinoic acid response element in hypoxia-inducible factor-1α promoter upon treatment with all-trans retinoic acid and 16,16-dimethyl-prostaglandin E(2). Since intracellular prostaglandin E(2) mediates hypoxia-inducible factor-1α up-regulation in normoxia in HK-2 cells, we next investigated and confirmed, its role in the up-regulation of retinoic acid receptor-β in normoxia by hypoxia-inducible factor-1α-inducing agents all-trans retinoic acid, interleukin-1β and 16,16-dimethyl-prostaglandin E(2) by inhibiting cyclooxygenases, prostaglandin influx transporter or EP receptors. Interestingly, the hypoxia-induced increase in retinoic acid receptor-β expression and accumulation of hypoxia-inducible factor-1α was also blocked by the inhibitors tested. This is the first time, to our knowledge, that retinoic acid receptor-β signalling is involved in the control of the expression of transcription factor hypoxia-inducible factor-1α in both normoxia and hypoxia and that retinoic acid receptor-β expression is found to be strictly regulated by intracellular prostaglandin E(2). Given the relevance of hypoxia-inducible factor-1α in the kidney in terms of tumorigenesis, progressive renal failure, production of erythropoietin and protection in several models of renal disease, our results open new therapeutic opportunities on the control of hypoxia-inducible factor-1α based upon the pharmacological modulation of retinoic acid receptor-β, either directly or through the control of intracellular prostaglandin E(2) levels/signalling.
我们先前在人肾近端小管 HK-2 细胞中发现，缺氧和全反式视黄酸诱导的缺氧诱导因子-1α上调伴随着视黄酸受体-β的上调。在这里，我们首先研究了缺氧诱导因子-1α的表达是否依赖于视黄酸受体-β，我们的结果证实了这一点，因为 (i) 缺氧诱导因子-1α诱导剂缺氧、缺氧模拟剂去铁胺、全反式视黄酸和白细胞介素-1β增加了视黄酸受体-β的表达，(ii) 缺氧诱导因子-1α的上调被视黄酸受体-β拮抗剂 LE-135 或 siRNA 视黄酸受体-β所阻止，(iii) 在用全反式视黄酸和 16,16-二甲基-前列腺素 E(2)处理时，视黄酸受体-β直接结合到缺氧诱导因子-1α启动子中的视黄酸反应元件上。由于细胞内前列腺素 E(2)在 HK-2 细胞的常氧条件下介导缺氧诱导因子-1α的上调，因此我们接下来研究并证实了，在常氧条件下，缺氧诱导因子-1α诱导剂全反式视黄酸、白细胞介素-1β和 16,16-二甲基-前列腺素 E(2)通过抑制环加氧酶、前列腺素流入转运体或 EP 受体上调视黄酸受体-β的作用。有趣的是，用所测试的抑制剂也可以阻断缺氧诱导的视黄酸受体-β表达增加和缺氧诱导因子-1α的积累。据我们所知，这是第一次发现视黄酸受体-β信号参与常氧和缺氧条件下转录因子缺氧诱导因子-1α表达的控制，并且发现视黄酸受体-β的表达受到细胞内前列腺素 E(2)的严格调节。鉴于缺氧诱导因子-1α在肾脏肿瘤发生、进行性肾衰竭、促红细胞生成素产生和几种肾脏疾病模型中的保护作用，我们的结果为基于视黄酸受体-β的药理学调节来控制缺氧诱导因子-1α提供了新的治疗机会，无论是直接调节还是通过控制细胞内前列腺素 E(2)水平/信号。
