Prenatal retinoic acid up-regulates pulmonary gene expression of COUP-TFII, FOG2, and GATA4 in pulmonary hypoplasia
Prenatal retinoic acid up-regulates pulmonary gene expression of COUP-TFII, FOG2, and GATA4 in pulmonary hypoplasia
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DOI：
10.1016/j.jpedsurg.2009.04.027
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发表时间：
2009-10-01
影响因子：
2.4
通讯作者：
Puri, Prem
中科院分区：
文献类型：
--
作者：
Doi, Takashi;Sugimoto, Kaoru;Puri, Prem
目的：维甲酸在肺发育中起重要作用。最近，产前治疗与维甲酸（RA）已被报道刺激肺泡发育不良的肺在硝基氟苯模型的先天性疝（CDH）。鸡卵清蛋白上游启动子-转录因子II（COUP-TFII）是类固醇/甲状腺激素受体超家族中的转录因子，靶向消融COUP-TFII可导致小鼠CDH和相关肺发育不全。加塔之友2（FOG 2）是一种含锌指的蛋白，其调节加塔蛋白的转录活性。GATA 4是DNA结合蛋白家族的成员，其存在于许多基因的启动子区域中。COUP-TFII、FOG 2和GATA 4基因受类维生素A信号通路调节，分别位于染色体15 q26、8 q23和8p23.1上，这些区域据报道在CDH个体中缺失。本研究的目的是研究COUP-TFII，FOG 2，和GATA 4的肺基因表达在除草醚模型CDH.Materials和方法：妊娠大鼠暴露于橄榄油或100毫克除草醚在妊娠第9天（D9）。在D18、D19和D20天腹膜内给予5 mg/kg RA。在D21通过剖腹产回收胎仔，并在显微镜下仔细检查横膈膜是否存在疝。左肺取自CDH胎儿和对照，并分为四组：对照组（n = 9）、对照+ RA组（n = 9）、CDH组（n = 9）和CDH + RA组（n = 9）。结果：COUP-TFII、FOG 2和GATA 4的相对mRNA表达水平在CDH + RA肺中与对照、对照+ RA和CDH相比显著增加结论：在CDH的硝苯酰草胺模型中，用维甲酸进行产前治疗后，COUP-TFII、FOG 2和GATA 4的肺基因表达上调，表明RA可能具有调节肺生长的治疗潜力。此外，这些结果支持了这些蛋白质共同调节下游靶基因的概念，这些基因在肺的发育中起重要作用。(C)2009 Elsevier Inc. All rights reserved.
Purpose: Retinoids play an important role in lung development. Recently, prenatal treatment with retinoic acid (RA) has been reported to stimulate alveologenesis in hypoplastic lungs in the nitrofen model of congenital diaphragmatic hernia (CDH). Chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) is a transcription factor in the steroid/thyroid hormone receptor superfamily, and targeted ablation of COUP-TFII causes CDH and associated lung hypoplasia in mice. Friend of GATA 2 (FOG2) is a zinc finger-containing protein that modulates the transcriptional activity of GATA proteins. GATA4 is a member of a family of DNA-binding proteins, which is found in the promoter regions of many genes. The COUP-TFII, FOG2, and GATA4 genes, regulated by the retinoid signaling pathway, are located on chromosomes 15q26, 8q23, and 8p23.1 respectively, regions reported to be deleted in individuals with CDH. The aim of this Study was to examine the pulmonary gene expression of COUP-TFII, FOG2, and GATA4 in the nitrofen model of CDH.Materials and Methods: Pregnant rats were exposed to either olive oil or 100 mg nitrofen on day 9 of gestation (D9). 5 mg/kg of RA was given intraperitoneally on days D 18, D 19, and D20. The fetuses were recovered by caesarean section on D21, and the diaphragm was carefully examined for the presence of a hernia under a microscope. Left lungs were obtained from CDH fetuses and controls and divided into four groups: control (n = 9), control + RA (n = 9), CDH (n = 9), and CDH + RA (n = 9). The relative mRNA expression levels of COUP-TFII, FOG2, and GATA4 were analyzed in each lung by real-time reverse transcriptase-polymerase chain reaction from cDNA generated by mRNA from pulmonary total RNA.Results: The relative mRNA expression levels of COUP-TFII, FOG2, and GATA4 were significantly increased in CDH + RA lungs compared to control, control + RA, and CDH (P < .05).Conclusions: Up-regulation of pulmonary gene expression of COUP-TFII, FOG2, and GATA4 after prenatal treatment with retinoic acid in the nitrofen model of CDH suggests that RA may have a therapeutic potential in modulating lung growth. Furthermore, these results support the concept that these proteins work together to regulate downstream target genes that play an important role in the development of lung. (C) 2009 Elsevier Inc. All rights reserved.