Coordinated up-regulation by hypoxia of adrenomedullin and one of its putative receptors (RDC-1) in cells of the rat blood-brain barrier
Coordinated up-regulation by hypoxia of adrenomedullin and one of its putative receptors (RDC-1) in cells of the rat blood-brain barrier
复制标题
DOI：
10.1074/jbc.m006512200
复制
发表时间：
2000-12-22
影响因子：
4.8
通讯作者：
Frelin, C
中科院分区：
文献类型：
--
作者：
Ladoux, A;Frelin, C
肾上腺髓质素（ADM）是一种强有力的促炎肽，在脓毒症和缺血时产生。我们在这里证明，缺氧诱导的ADM mRNA和蛋白质表达在培养的星形胶质细胞和内皮细胞从大鼠脑微血管的时间依赖性增加。基因报告分析表明，ADM基因转录增加了2倍，当ADM启动子缺失其缺氧反应元件时，ADM基因转录被抑制。缺氧增加了7倍的稳定性预形成的ADM mRNA。大鼠脑微血管表达编码不同假定的ADM受体的mRNA，但它们不响应于外源性ADM和降钙素基因相关肽的cAMP的形成。相反，ADM和降钙素基因相关肽增加了星形胶质细胞中cAMP的形成，缺氧后其作用增强约2倍。编码三种假定ADM受体（L1孤儿受体、RDC-1和降钙素受体样受体）和辅助蛋白（受体活性修饰蛋白）的信使RNA物质存在于星形胶质细胞中。缺氧选择性上调RDC-1受体mRNA的表达。结果表明，ADM和RDC-1是缺氧敏感基因，RDC-1受体可能介导ADM在缺氧星形胶质细胞中的某些作用。
Adrenomedullin (ADM) is a potent hypotensive peptide, which is produced during sepsis and ischemia. We demonstrate here that hypoxia induced a time-dependent increase of both ADM mRNA and protein expressions in cultured astrocytes and endothelial cells from rat brain microvessels. Gene reporter analyses showed a 2-fold increase in ADM gene transcription which was suppressed when the ADM promoter was deleted of its hypoxia responsive element. Hypoxia increased 7-fold the stability of pre-formed ADM mRNAs. Rat brain microvessels expressed mRNAs coding for the different putative ADM receptors but they did not respond to exogenous ADM and calcitonin gene-related peptide by the formation of cAMP. In contrast, ADM and calcitonin gene-related peptide increased the formation of cAMP in astrocytes and their actions were potentiated about 2-fold after hypoxia. Messenger RNA species coding for three putative ADM receptors (the L1 orphan receptor, RDC-1, and calcitonin receptor-like receptor) and accessory proteins (receptor-activity modifying proteins) were present in astrocytes. Hypoxia selectively up-regulated expression of RDC-1 receptor mRNAs. The results indicate that ADM and RDC-1 are hypoxia-sensitive genes and that RDC-1 receptors may mediate some actions of ADM in hypoxic astrocytes.