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

点击翻译按钮获取中文摘要

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.