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Role of nitric oxide in the pathogenesis of diabetes-induced congenital malformations

一氧化氮在糖尿病先天性畸形发病机制中的作用

基本信息

批准号：
16590875
负责人：
MURASE Takashi
金额：
$ 2.24万
依托单位：
Nagoya University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16590875/
关键词：
diabetes mellitus malformation nitric oxide apoptosis neural tube defect

项目摘要

Maternal diabetes during pregnancy is known to increase the risk for congenital malformations in offspring. In the present study, we examined the role of NO in the pathogenesis of diabetic embryopathy by using a mouse model of diabetic pregnancy. Female mice were rendered hyperglycemic by an intraperitoneal injection of streptozotocin, and mated. Pregnant diabetic mice were intraperitoneally injected with L-NAME, a non-selective NOS inhibitor, or ONO1714, a selective iNOS inhibitor, from gestational day 7 through day 10. On gestational day 18, fetuses were examined for congenital malformations. The incidence of neural tube defects (NTDs) such as spina bifida and exencephaly were 32% in diabetic embryos, whereas both L-NAME and ONO1714 markedly reduced it to 6%. The incidences of cardiovascular malformations and skeletal malformations were also reduced by L-NAME or ONO1714 as well. No NTDs were observed in fetuses from diabetic iNOS knockout mice. In E9.5 embryos of diabetic mice, immunostaining for iNOS and TUNEL positive apoptotic cells were observed in the neural tube cells. Immunostaining for nitrotyrosine, a marker for NO-induced tissue damage, was also observed in the neural tube of diabetic embryos at E9.5. These results demonstrate that overproduction of NO by the increased iNOS activity during organogenesis in diabetic embryos has a crucial role in the pathogenesis of diabetes-induced congenital malformations by inducing apoptosis of neural tube cells.

孕妇在怀孕期间患糖尿病会增加后代先天性畸形的风险。在本研究中，我们通过糖尿病妊娠小鼠模型研究了NO在糖尿病胚胎病发病机制中的作用。雌性小鼠通过腹腔注射链脲佐菌素导致高血糖，并进行交配。从妊娠第7天至第10天，妊娠糖尿病小鼠腹腔注射非选择性NOS抑制剂L-NAME或选择性iNOS抑制剂ONO1714。在妊娠第18天，检查胎儿是否有先天性畸形。糖尿病胚胎神经管缺陷（NTDs）如脊柱裂和畸形发生率为32%，而L-NAME和ONO1714显著降低至6%。L-NAME或ONO1714也可降低心血管畸形和骨骼畸形的发生率。糖尿病iNOS敲除小鼠胎儿未见NTDs。在糖尿病小鼠E9.5胚胎中，观察到神经管细胞中iNOS和TUNEL阳性凋亡细胞的免疫染色。在E9.5时，糖尿病胚胎的神经管中也观察到硝基酪氨酸（no诱导组织损伤的标志物）的免疫染色。这些结果表明，在糖尿病胚胎器官发生过程中，通过增加iNOS活性而过量产生NO，通过诱导神经管细胞凋亡在糖尿病诱导先天性畸形的发病机制中起着至关重要的作用。