Nuclear receptor LXRalpha is involved in cAMP-mediated human renin gene expression.
Nuclear receptor LXRalpha is involved in cAMP-mediated human renin gene expression.
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核受体 LXRα 参与 cAMP 介导的人肾素基因表达。
DOI：
10.1016/j.mce.2004.07.005
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发表时间：
2004
影响因子：
4.1
通讯作者：
Dzau,VictorJ
中科院分区：
文献类型：
--
作者：
Tamura,Kouichi;Chen,YuqingE;Tanaka,Yutaka;Sakai,Masashi;Tsurumi,Yuko;Koide,Yuichi;Kihara,Minoru;Pratt,RichardE;Horiuchi,Masatsugu;Umemura,Satoshi;Dzau,VictorJ
cAMP信号通路在肾素基因的调节中起着至关重要的作用，但所涉及的机制仍然知之甚少。我们将Renin基因调节的研究重点放在人类Renin启动子中独特的cAMP反应元件（huREN/CNRE，-135至-107）上。我们已经克隆了一个与这种独特的CNRE结合的蛋白质，并证明该蛋白质是肝X受体-α（LXRα），核受体家族的转录因子。LXRα在人肾素产生细胞Calu-6中的瞬时表达增加了人肾素启动子的cAMP诱导。类似地，LXRα稳定转染的Calu-6细胞表现出增加的cAMP诱导的肾素启动子以及内源性肾素基因。huREN/CNRE的定点突变破坏了LXRα的结合，降低了cAMP诱导的人肾素启动子的转录活性。此外，我们证明了来自人肾小球细胞（肾脏中肾素的主要产生部位）的LXRα与体内huREN/CNRE的结合。这些结果表明LXRα通过与CNRE结合在cAMP介导的人肾素基因转录调控中起重要作用。
The cAMP-signaling pathway plays a crucial role in the regulation of the renin gene, but the mechanism involved remains poorly understood. We have focused our studies of renin gene regulation on the unique cAMP responsive element (huREN/CNRE, −135 to −107) in the human renin promoter. We have cloned a protein that binds to this unique CNRE and demonstrated that this protein is liver X receptor-α (LXRα), a transcriptional factor of the nuclear receptor family. Transient expression of LXRα in human renin-producing Calu-6 cells increased cAMP inducibility of human renin promoter. Similarly, LXRα-stably transfected Calu-6 cells exhibited increased cAMP inducibility of renin promoter as well as the endogenous renin gene. Site-directed mutation of huREN/CNRE, which disrupted LXRα binding, decreased cAMP-induced transcriptional activity of human renin promoter. Furthermore, we demonstrated that the binding of LXRα derived from human juxtaglomerular cells, the main production site of renin in the kidney, to the huREN/CNRE in vivo. These results suggest that LXRα plays an important role in the cAMP-mediated regulation of human renin gene transcription by binding to CNRE.