MOLECULAR MECHANISM OF HUMAN RENIN AND C-MYC, GENES REGULATION THROUGH NUCLEAR RECEPTOR LXR

人肾素和C-MYC的分子机制、核受体LXR的基因调控

• 批准号: 15590983
• 负责人: TAMURA Kouichi
• 金额: $ 2.24万
• 依托单位: YOKOHAMA CITY UNIVERSITY, SCHOOL OF MEDICINE
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590983/
• 关键词: Renin; Nuclear receptor; Liver X receptor alpha (LXRα); Promoter; Transcriptional regulation; Cyclic AMP; Oxidized cholesterol; c-myc

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 LXRa 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. In parallel experiments, we demonstrated that LXRα can also bind to the homologous CNRE in the c-myc promoter. cAMP promotes transcription through c-myc/CNRE : LXRa interaction in LXRα-transiently transfected cells and increases c-myc mRNA expression in stably transfected cells. Identification of LXRα as a novel cAMP responsive nuclear modulator of renin and c-myc expression not only has cardiovascular significance but may have generalized implication in the regulation of gene transcription.

cAMP 信号通路在肾素基因的调节中发挥着至关重要的作用，但所涉及的机制仍知之甚少。我们将肾素基因调控的研究重点放在人肾素启动子中独特的 cAMP 响应元件（huREN/CNRE，-135 至 -107）上。我们克隆了一种与这种独特的 CNRE 结合的蛋白质，并证明这种蛋白质是肝 X 受体-α (LXRα)，它是核受体家族的转录因子。 LXRα 在产生人肾素的 Calu-6 细胞中的瞬时表达增加了人肾素启动子的 cAMP 诱导能力。同样，LXRα 稳定转染的 Calu-6 细胞表现出肾素启动子以及内源肾素基因的 cAMP 诱导能力增加。 huREN/CNRE 的定点突变破坏了 LXRα 结合，降低了 cAMP 诱导的人肾素启动子转录活性。此外，我们证明了源自人肾小球旁细胞（肾脏中肾素的主要产生位点）的 LXRa 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节中发挥重要作用。在平行实验中，我们证明LXRα也可以与c-myc启动子中的同源CNRE结合。 cAMP 通过 LXRα 瞬时转染细胞中的 c-myc/CNRE : LXRa 相互作用促进转录，并增加稳定转染细胞中的 c-myc mRNA 表达。 LXRα 被鉴定为肾素和 c-myc 表达的新型 cAMP 反应性核调节剂，不仅具有心血管意义，而且可能对基因转录的调节具有普遍意义。

项目成果

Alterations in renal endothelial nitric oxide synthase expression by salt diet in angiotensin type-1a receptor gene knockout mice

血管紧张素1a型受体基因敲除小鼠盐饮食对肾内皮一氧化氮合酶表达的影响

• 发表时间: 2004
• 期刊: J Am Soc Nephrol 15
• 作者: Sato K;et al.
• 通讯作者: et al.

Analysis of Factors that Affect Short-Term Blood Pressure Variability in Patients with Chronic Renal Failure.

影响慢性肾功能衰竭患者短期血压变异的因素分析。

• 发表时间: 2005
• 期刊: Clinical and Experimental Hypertension 27
• 作者: Sakai M;Tamura K;et al.
• 通讯作者: et al.

Nuclear receptor LXRalpha is involved in cAMP-mediated human renin gene expression.

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
• 发表时间: 2004
• 期刊: Molecular and cellular endocrinology
• 影响因子: 4.1
• 作者: Tamura,Kouichi;Chen,YuqingE;Tanaka,Yutaka;Sakai,Masashi;Tsurumi,Yuko;Koide,Yuichi;Kihara,Minoru;Pratt,RichardE;Horiuchi,Masatsugu;Umemura,Satoshi;Dzau,VictorJ
• 通讯作者: Dzau,VictorJ

Tamura K, et al.: "A case of acute renal failure due to cholesterol crystal embolism treated with LDL aphere sis followed by corticosteroid and candesartan"Clin Exp Nephrol. 7. 67-71 (2003)

Tamura K 等人：“一例因胆固醇晶体栓塞而导致急性肾衰竭的病例，采用 LDL 单采术治疗，然后采用皮质类固醇和坎地沙坦治疗”Clin Exp Nephrol。

Alterations in renal endothelial nitric oxide synthase expression by salt diet in angiotensin type-1 a receptor gene-knockout mice

血管紧张素1a型受体基因敲除小鼠盐饮食对肾内皮一氧化氮合酶表达的改变

• 发表时间: 2004
• 期刊: J Am Soc Nephrol. 15
• 作者: Sato;K.;Kihara;M.;Hashimoto;T.;Matsushita;K.;Koide;Y.;Tamura;K.;Hirawa;N.;Toya;Y.;Fukamizu;A.;Umemura;S.
• 通讯作者: S.