Peroxynitrites and impaired modulation of nitric oxide concentrations in embryos from diabetic rats during early organogenesis.
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 delta(12,14)prostaglandin 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.
Jawerbaum
A
A
Centro de Estudios Farmacológicos y Botánicos (CEFYBO), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Serrano 669, (C1414DEM) Buenos Aires, Argentina. a.jawerbaum@abaconet.com.ar
Higa
R
R
White
V
V
Capobianco
E
E
Pustovrh
C
C
Sinner
D
D
Martínez
N
N
González
E
E
D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000737:chemistry / Q000378:metabolism*; D019332:Endothelin-1 / Q000032:analysis; D005260:Female; D007150:Immunohistochemistry / Q000379:methods; D009566:Nitrates / Q000032:analysis; D009569:Nitric Oxide / Q000378:metabolism*; D009573:Nitrites / Q000032:analysis; D038081:Organogenesis / Q000502:physiology*; D011247:Pregnancy; D011254:Pregnancy in Diabetics / Q000378:metabolism*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000032:analysis
C477819:15-deoxyprostaglandin J2; D019332:Endothelin-1; D009566:Nitrates; D009573:Nitrites; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D015230:Prostaglandin D2