Prevention of neural tube defects by loss of function of inducible nitric oxide synthase in fetuses of a mouse model of streptozotocin-induced diabetes

Yoshihisa Sugimura, T. Murase, K. Oyama, A. Uchida, N. Sato, S. Hayasaka, Y. Kano, Y. Takagishi, Y. Hayashi, Y. Oiso, Y. Murata

Research output: Contribution to journalArticle

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Abstract

Aims/hypothesis: Maternal diabetes during pregnancy increases the risk of congenital malformations such as neural tube defects (NTDs). Although the mechanism of this effect is uncertain, it is known that levels of nitric oxide synthase (NOS) and nitric oxide are elevated in embryos of a mouse model of diabetes. We postulated that overproduction of nitric oxide causes diabetes-induced congenital malformations and that inhibition of inducible NOS (iNOS) might prevent diabetic embryopathy. Methods: Mice were rendered hyperglycaemic by intraperitoneal injection of streptozotocin. The incidence of congenital malformations including NTDs was evaluated on gestational day 18.5. We assessed the involvement of iNOS in diabetes-induced malformation by administering ONO-1714, a specific inhibitor of iNOS, to pregnant mice with streptozotocin-induced diabetic mice and by screening mice with iNOS deficiency due to genetic knockout (iNos -/-). Results: ONO-1714 markedly reduced the incidence of congenital anomalies, including NTDs, in fetuses of a mouse model of diabetes. It also prevented apoptosis in the head region of fetuses, indicating that iNOS is involved in diabetes-related congenital malformations. Indeed, no NTDs were observed in fetuses of diabetic iNos -/- mice and the incidence of other malformations was also markedly reduced. Conclusions/interpretation: We conclude that increased iNOS activity during organogenesis plays a crucial role in the pathogenesis of diabetes-induced malformations and suggest that inhibitors of iNOS might help prevent malformations, especially NTDs, in diabetic pregnancy.

Original languageEnglish
Pages (from-to)962-971
Number of pages10
JournalDiabetologia
Volume52
Issue number5
DOIs
Publication statusPublished - 01-05-2009

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Experimental Diabetes Mellitus
Neural Tube Defects
Nitric Oxide Synthase Type II
Fetus
Streptozocin
Incidence
Nitric Oxide
Fetal Diseases
Pregnancy in Diabetics
Organogenesis
Intraperitoneal Injections
Nitric Oxide Synthase
Embryonic Structures
Head
Mothers
Apoptosis
Pregnancy

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Sugimura, Yoshihisa ; Murase, T. ; Oyama, K. ; Uchida, A. ; Sato, N. ; Hayasaka, S. ; Kano, Y. ; Takagishi, Y. ; Hayashi, Y. ; Oiso, Y. ; Murata, Y. / Prevention of neural tube defects by loss of function of inducible nitric oxide synthase in fetuses of a mouse model of streptozotocin-induced diabetes. In: Diabetologia. 2009 ; Vol. 52, No. 5. pp. 962-971.
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abstract = "Aims/hypothesis: Maternal diabetes during pregnancy increases the risk of congenital malformations such as neural tube defects (NTDs). Although the mechanism of this effect is uncertain, it is known that levels of nitric oxide synthase (NOS) and nitric oxide are elevated in embryos of a mouse model of diabetes. We postulated that overproduction of nitric oxide causes diabetes-induced congenital malformations and that inhibition of inducible NOS (iNOS) might prevent diabetic embryopathy. Methods: Mice were rendered hyperglycaemic by intraperitoneal injection of streptozotocin. The incidence of congenital malformations including NTDs was evaluated on gestational day 18.5. We assessed the involvement of iNOS in diabetes-induced malformation by administering ONO-1714, a specific inhibitor of iNOS, to pregnant mice with streptozotocin-induced diabetic mice and by screening mice with iNOS deficiency due to genetic knockout (iNos -/-). Results: ONO-1714 markedly reduced the incidence of congenital anomalies, including NTDs, in fetuses of a mouse model of diabetes. It also prevented apoptosis in the head region of fetuses, indicating that iNOS is involved in diabetes-related congenital malformations. Indeed, no NTDs were observed in fetuses of diabetic iNos -/- mice and the incidence of other malformations was also markedly reduced. Conclusions/interpretation: We conclude that increased iNOS activity during organogenesis plays a crucial role in the pathogenesis of diabetes-induced malformations and suggest that inhibitors of iNOS might help prevent malformations, especially NTDs, in diabetic pregnancy.",
author = "Yoshihisa Sugimura and T. Murase and K. Oyama and A. Uchida and N. Sato and S. Hayasaka and Y. Kano and Y. Takagishi and Y. Hayashi and Y. Oiso and Y. Murata",
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Sugimura, Y, Murase, T, Oyama, K, Uchida, A, Sato, N, Hayasaka, S, Kano, Y, Takagishi, Y, Hayashi, Y, Oiso, Y & Murata, Y 2009, 'Prevention of neural tube defects by loss of function of inducible nitric oxide synthase in fetuses of a mouse model of streptozotocin-induced diabetes', Diabetologia, vol. 52, no. 5, pp. 962-971. https://doi.org/10.1007/s00125-009-1312-0

Prevention of neural tube defects by loss of function of inducible nitric oxide synthase in fetuses of a mouse model of streptozotocin-induced diabetes. / Sugimura, Yoshihisa; Murase, T.; Oyama, K.; Uchida, A.; Sato, N.; Hayasaka, S.; Kano, Y.; Takagishi, Y.; Hayashi, Y.; Oiso, Y.; Murata, Y.

In: Diabetologia, Vol. 52, No. 5, 01.05.2009, p. 962-971.

Research output: Contribution to journalArticle

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T1 - Prevention of neural tube defects by loss of function of inducible nitric oxide synthase in fetuses of a mouse model of streptozotocin-induced diabetes

AU - Sugimura, Yoshihisa

AU - Murase, T.

AU - Oyama, K.

AU - Uchida, A.

AU - Sato, N.

AU - Hayasaka, S.

AU - Kano, Y.

AU - Takagishi, Y.

AU - Hayashi, Y.

AU - Oiso, Y.

AU - Murata, Y.

PY - 2009/5/1

Y1 - 2009/5/1

N2 - Aims/hypothesis: Maternal diabetes during pregnancy increases the risk of congenital malformations such as neural tube defects (NTDs). Although the mechanism of this effect is uncertain, it is known that levels of nitric oxide synthase (NOS) and nitric oxide are elevated in embryos of a mouse model of diabetes. We postulated that overproduction of nitric oxide causes diabetes-induced congenital malformations and that inhibition of inducible NOS (iNOS) might prevent diabetic embryopathy. Methods: Mice were rendered hyperglycaemic by intraperitoneal injection of streptozotocin. The incidence of congenital malformations including NTDs was evaluated on gestational day 18.5. We assessed the involvement of iNOS in diabetes-induced malformation by administering ONO-1714, a specific inhibitor of iNOS, to pregnant mice with streptozotocin-induced diabetic mice and by screening mice with iNOS deficiency due to genetic knockout (iNos -/-). Results: ONO-1714 markedly reduced the incidence of congenital anomalies, including NTDs, in fetuses of a mouse model of diabetes. It also prevented apoptosis in the head region of fetuses, indicating that iNOS is involved in diabetes-related congenital malformations. Indeed, no NTDs were observed in fetuses of diabetic iNos -/- mice and the incidence of other malformations was also markedly reduced. Conclusions/interpretation: We conclude that increased iNOS activity during organogenesis plays a crucial role in the pathogenesis of diabetes-induced malformations and suggest that inhibitors of iNOS might help prevent malformations, especially NTDs, in diabetic pregnancy.

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