Departamento de Fisiología, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain.
Int J Biochem Cell Biol. 2011 Aug;43(8):1198-207. doi: 10.1016/j.biocel.2011.04.013. Epub 2011 Apr 28.
Hypoxia-inducible factor-1α (HIF-1α) and all-trans retinoic acid (ATRA) afford protection in several experimental models of kidney disease. HIF-1α protein is degraded under normoxia but stabilized by hypoxia, which activates its transcription factor function. ATRA activates another set of transcription factors, the retinoic acid receptors (RAR) α, β and γ, which mediate its effects on target genes. ATRA also up-regulates the expression of RAR α, β and γ at the transcriptional level. Here we demonstrate the presence of mutual regulation of hypoxic and retinoic acid related signalling in tubular proximal cells. In human proximal tubular HK-2 cells we have found that: (i) ATRA treatment induces HIF-1α under normoxic conditions and also synergizes with hypoxia leading to the over-expression of HIF-1α and vascular endothelial growth factor-A, a HIF-1α-regulated renal protector. ATRA-induced HIF-1α expression involved stabilization of HIF-1α mRNA but not of HIF-1α protein. (ii) Expression of HIF-1α is an absolute requirement for the transcriptional up-regulation of RARβ by ATRA. Transfection with HIF-1α siRNA abolished the induction by ATRA of the expression of both RARβ mRNA and protein while treatment with HIF-1α inhibitor YC-1 results in the abolishment of ATRA-induced activity of a retinoic acid-response element (RARE) construct from the RARβ promoter. (iii) Hypoxia up-regulates RARβ through HIF-1α since this effect was inhibited by HIF-1α knockdown. In contrast to ATRA-induced RARβ up-regulation, induction of RARβ expression by ATRA did not involve transcriptional up-regulation as hypoxia did not increase the expression of RARβ mRNA or the activity of the RARE construct. These results suggest the presence of crosstalk between hypoxia/HIF-1α and ATRA/RARβ that may be physiologically and pharmacologically relevant.
缺氧诱导因子-1α（HIF-1α）和全反式维甲酸（ATRA）可在几种肾脏疾病的实验模型中提供保护。HIF-1α 蛋白在常氧条件下被降解，但在缺氧条件下被稳定，从而激活其转录因子功能。ATRA 激活另一组转录因子，即视黄酸受体（RAR）α、β和γ，介导其对靶基因的作用。ATRA 还在转录水平上上调 RAR α、β和γ的表达。在这里，我们证明了管状近端细胞中缺氧和维甲酸相关信号之间存在相互调节。在人近端肾小管 HK-2 细胞中，我们发现：（i）ATRA 处理在常氧条件下诱导 HIF-1α，并且与缺氧协同作用导致 HIF-1α 和血管内皮生长因子-A 的过表达，HIF-1α 调节的肾脏保护剂。ATRA 诱导的 HIF-1α 表达涉及 HIF-1α mRNA 的稳定，但不涉及 HIF-1α 蛋白的稳定。（ii）HIF-1α 的表达是 ATRA 对 RARβ 转录上调的绝对要求。用 HIF-1α siRNA 转染可消除 ATRA 对 RARβ mRNA 和蛋白表达的诱导，而用 HIF-1α 抑制剂 YC-1 处理则可消除 ATRA 诱导的 RARβ 启动子上的视黄酸反应元件（RARE）构建体的活性。（iii）缺氧通过 HIF-1α 上调 RARβ，因为这种效应被 HIF-1α 敲低所抑制。与 ATRA 诱导的 RARβ 上调不同，ATRA 诱导的 RARβ 表达不涉及转录上调，因为缺氧不会增加 RARβ mRNA 的表达或 RARE 构建体的活性。这些结果表明，缺氧/HIF-1α 和 ATRA/RARβ 之间存在串扰，这可能在生理和药理学上具有相关性。
