Neural tube defects (NTDs) in infants of diabetic mothers are associated with increased programmed cell death (apoptosis) in the neuroepithelium during early embryogenesis leading to diabetic embryopathy. Recent data suggests that protein kinase Cβ2 (PKCβ2) plays a role in diabetic embryopathy. We propose that it may regulate apoptosis. Apoptosis in diabetic embryopathy is associated with increased caspase-8 and -3 activity and increased tBid cleavage.
To test this hypothesis, mouse embryos at embryonic day 7.5 (E7.5) were cultured under hyperglycemic conditions (400 mg glucose/dl) in the presence or absence of the PKCβ2 inhibitor (PKCβ-I, 50 nM) for 48 h.
The neural tube malformation rate was 58.3% in embryos maintained under hyperglycemic conditions. The high rate of neural tube malformation was associated with increased apoptosis including activation of caspase-8 and -3, and increased Bid cleavage to form tBid. Treatment with PKC inhibitor reduced the malformation rate to 26.7% which is similar to the rate observed in embryos maintained under euglycemic conditions (150 mg glucose/dl), and also reduced caspase activation and Bid cleavage to control levels.
These findings indicate that PKCβ2 is required for hyperglycemia-induced neural tube malformation via a mechanism that involves regulation of caspase-8 associated apoptosis.
© 2011 Mosby, Inc. Published by Elsevier Inc. All rights reserved.