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Significance of increase in aquaporin 5 expression in respiratory system

呼吸系统中水通道蛋白5表达增加的意义

基本信息

批准号：
18590061
负责人：
ISOHAMA Yoichiro
金额：
$ 2.5万
依托单位：
Kumamoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590061/
关键词：
alveolar epithelial cell gas exchange aquaporin nitric oxide DNA methylation CO_2がス透過性

项目摘要

O_2 and CO_2 gas transport through plasma membrane is important to maintain normal respiration between alveolar space and blood flow. We have previously indicated that aquaporins (AQPs) enhances movement of CO_2 gas, as well as water, across plasma membrane, and suggested that the increase in AQP expression might enhance gas exchange at alveoli. In this study, therefore, we first examined the mechanism of AQP5 expression in alveolar epithelial cells. It has been defined that promoter region of AQP5 gene was methylated in the cell types without AQP5, whereas it was demethylated in alveolar type I cells. The methylation of AQP5 DNA significantly decreased its transcriptional activity and the binding to Sp1 transcription factor. We have also found all-trans retinoic acid as a new AQP5 inducer. Retinoic acid increased AQP5 transcription through the activation of Sp1. In addition, we examined the effect of nitric oxide (NO), which is an important inflammatory mediator, on AQP5 activity. NO decreased AQP5 activity by S-nitrosylation of cystein residue in the water pore of AQP5.We finally, prepared CHO cells which stably express AQP5. The growth and morphology were same with those of control CHO cells without AQP5. However, the apoptosis induced by hypoxia was significantly less than that in control cells. Interestingly, glucose deprivation induced apoptosis equally in both cells, suggesting increased gas metabolism by AQP5 might inhibit hypoxia-induced apoptosis in AQP5-expressing cells. These findings are useful to consider the new strategies to enhance gas exchange at alveolar-blood barrier in various respiratory diseases.

O_2和CO_2气体通过质膜的转运对维持肺泡腔和血流之间的正常呼吸起着重要作用。我们以前的研究表明，水通道蛋白（AQP）增强了CO_2气体和水的跨膜运动，并认为AQP表达的增加可能增强了肺泡的气体交换。因此，在本研究中，我们首先研究了肺泡上皮细胞中AQP 5表达的机制。已经确定，AQP 5基因启动子区在无AQP 5的细胞类型中是甲基化的，而在肺泡I型细胞中是去甲基化的。AQP 5 DNA甲基化显著降低其转录活性和与转录因子Sp1的结合。我们还发现全反式维甲酸作为一种新的AQP 5诱导剂。视黄酸通过激活Sp1增加AQP 5的转录。此外，我们研究了一氧化氮（NO），这是一种重要的炎症介质，对AQP 5活性的影响。NO通过对AQP 5水孔中的半胱氨酸残基进行S-亚硝基化而降低AQP 5的活性。其生长和形态与不含AQP 5的对照CHO细胞相同。而缺氧诱导的细胞凋亡明显少于对照组。有趣的是，葡萄糖剥夺诱导的凋亡在两种细胞中相同，这表明AQP 5增加的气体代谢可能抑制缺氧诱导的AQP 5表达细胞的凋亡。这些发现有助于考虑在各种呼吸系统疾病中增强肺泡-血液屏障气体交换的新策略。