Demonstration of the essential role of protein kinase C isoforms in hyperglycemia-induced embryonic malformations.
To address the role of PKC isoforms in hyperglycemia-induced apoptosis and malformations in the embryos of diabetic pregnancies, expression of PKCalpha, beta1, beta 2, gamma, delta, epsilon, and zeta was examined in the neural tube of rat embryos and showed to overlap with the regions of increased apoptosis. Levels of activated (phosphorylated) PKCalpha , beta2, and delta were increased in the embryos of diabetic dams whereas those of PKCepsilon and zeta were decreased when compared with those in control groups. Cytosolic phospholipase A(2) (cPLA(2)) was also activated. Blocking the activity of PKCalpha , beta2, and delta using isoform-specific inhibitors in embryos cultured in hyperglycemia (40 mM) reduced malformation rates when compared with those in untreated hyperglycemic and euglycemic (8.3 mM) groups. These observations demonstrate that PKCalpha, beta2, and delta play an essential role in diabetic embryopathy. Activation of cPLA(2) was also decreased, suggesting that PKCs mediate the hyperglycemic effects through the cPLA(2)-phospholipid peroxidation pathway.
Zhiyong Zhao
Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA. zzhao@upi.umaryland.edu
Wu
Ying-King
YK
Reece
E Albert
EA
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D003921:Diabetes Mellitus, Experimental; D046149:Embryo Culture Techniques; D047108:Embryonic Development / Q000502:physiology; D005260:Female; D005315:Fetal Diseases / Q000201:enzymology* / Q000209:etiology / Q000517:prevention & control; D006943:Hyperglycemia / Q000150:complications*; D008297:Male; D054259:Neural Tube / Q000187:drug effects / Q000196:embryology / Q000201:enzymology*; D009436:Neural Tube Defects / Q000196:embryology / Q000201:enzymology* / Q000517:prevention & control; D054510:Phospholipases A2, Cytosolic / Q000378:metabolism* / Q000502:physiology; D010766:Phosphorylation; D011247:Pregnancy; D020033:Protein Isoforms; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology; D015017:Yolk Sac / Q000196:embryology / Q000201:enzymology
D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors; D011493:Protein Kinase C; D054510:Phospholipases A2, Cytosolic