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Peroxynitrites and impaired modulation of nitric oxide concentrations in embryos from diabetic rats during early organogenesis

Centro de Estudios Farmacológicos y Botánicos (CEFYBO), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Serrano 669, (C1414DEM) Buenos Aires, Argentina and ¹ Cincinnati Children’s Medical Center Research Foundation, Developmental Biology Department, 3333 Burnet Ave, Cincinnati, Ohio 45229, USA

Correspondence should be addressed to A Jawerbaum; Email: a.jawerbaum{at}abaconet.com.ar

Maternal diabetes significantly increases the risk of congenital malformation, a syndrome known as diabetic embryopathy. Nitric oxide (NO), implicated in embryogenesis, has been found elevated in embryos from diabetic rats during organogenesis. The developmental signaling molecules endothelin-1 (ET-1) and 15-deoxy ^12,14prostaglandin J₂ (15dPGJ₂) downregulate embryonic NO levels. In the presence of NO and superoxide, formation of the potent oxidant peroxynitrite may occur. Therefore, we investigated peroxynitrite-induced damage, ET-1 and 15dPGJ₂ concentrations, and the capability of ET-1, 15dPGJ₂ and prostaglandin E₂ (PGE₂) to regulate NO production in embryos from severely diabetic rats (streptozotocin-induced before pregnancy). We found intense nitrotyrosine immunostaining (an index of peroxynitrite-induced damage) in neural folds, neural tube and developing heart of embryos from diabetic rats (P < 0.001 vs controls). We also found reduced ET-1 (P < 0.001) and 15dPGJ₂ (P < 0.001) concentrations in embryos from diabetic rats when compared with controls. In addition, the inhibitory effect of ET-1, 15dPGJ₂ and PGE₂ on NO production found in control embryos was not observed in embryos from severely diabetic rats. In conclusion, both the demonstrated peroxynitrite-induced damage and the altered levels and function of multiple signaling molecules involved in the regulation of NO production provide supportive evidence of nitrosative stress in diabetic embryopathy.

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