Maternal diabetes in vivo and high glucose in vitro diminish GAPDH activity in rat embryos.
The aim of the present study was to investigate whether diabetic embryopathy may be associated with the inhibition of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) resulting from an excess of reactive oxygen species (ROS) in the embryo. Recent demonstrations of enhanced ROS production in mitochondria of bovine aortic endothelial cells exposed to high glucose have supported the idea that the pathogenesis of diabetic complications may involve ROS-induced GAPDH inhibition. We investigated whether a teratogenic diabetic environment also inhibits embryonic GAPDH activity and alters GAPDH gene expression and whether antioxidants diminish such GAPDH inhibition. In addition, we determined whether the inhibition of GAPDH with iodoacetate induces dysmorphogenesis, analogous to that caused by high glucose concentration, and whether antioxidants modulated the putative teratogenic effect of such direct GAPDH inhibition. We found that embryos from diabetic rats and embryos cultured in high glucose concentrations showed decreased activity of GAPDH (by 40-60%) and severe dysmorphogenesis on gestational days 10.5 and 11.5. GAPDH mRNA was decreased in embryos of diabetic rats compared to control embryos. Supplementing the high-glucose culture with the antioxidant N-acetylcysteine (NAC) increased GAPDH activity and diminished embryonic dysmorphogenesis. Embryos cultured with iodoacetate showed both decreased GAPDH activity and dysmorphogenesis; supplementing the culture with NAC increased both parameters toward normal values. In conclusion, dysmorphogenesis caused by maternal diabetes is correlated with ROS-induced inhibition of GAPDH in embryos, which could indicate that inhibition of GAPDH plays a causal role in diabetic embryopathy.
Wentzel
Parri
P
Department of Medical Cell Biology, Biomedical Center, Uppsala University, PO Box 571, SE-751 23 Uppsala, Sweden. parri.wentzel@medcellbiol.uu.se
Ejdesjö
Andreas
A
Eriksson
Ulf J
UJ
D000818:Animals; D002417:Cattle; D000013:Congenital Abnormalities / Q000196:embryology / Q000453:epidemiology; D003921:Diabetes Mellitus, Experimental / Q000097:blood*; D004622:Embryo, Mammalian / Q000201:enzymology; D005260:Female; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000235:genetics / Q000378:metabolism*; D006943:Hyperglycemia / Q000097:blood*; D009924:Organ Culture Techniques; D011247:Pregnancy; D011254:Pregnancy in Diabetics / Q000097:blood*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism
D017382:Reactive Oxygen Species; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases