Involvement of c-Jun N-terminal kinases activation in diabetic embryopathy.
The mechanisms for diabetic embryopathy are not well understood. JNK1/2 activation is increased in diabetic embryopathy, and antioxidants abolish JNK activation, and thus, ameliorate diabetic embryopathy. Phosphorylated SEK1 were significantly elevated in malformed embryos from diabetic mouse. In a dose-dependent manner, JNK inhibitor (SP600125) significantly reduced hyperglycemia-induced embryopathy. Malformation rates in embryos from the diabetic WT group were 15.6-fold higher than that in the non-diabetic WT control group. Jnk2 null mutant (JNKKO mice) was associated with a 71% reduction in the malformation rate of embryos under maternal diabetic conditions. Embryos cultured in 0.5mM sorbitol (JNK activator) had a malformation rate that was significantly higher than that of the control group. Pharmacological and genetic evidence from the present studies strongly support JNK activation being an indispensable mediator of diabetic embryopathy. JNK activation itself is sufficient to induce embryonic anomalies, and thus mimics the teratogenic effect of hyperglycemia.
Yang
Peixin
P
Department of Obstetrics, Gynecology & Reproductive Sciences, University of Maryland School of Medicine, 655 W. Baltimore Street, Baltimore, MD 21201, USA. Pyang@upi.umaryland.edu
Zhao
Zhiyong
Z
Reece
E Albert
EA
D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian / Q000002:abnormalities* / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005838:Genotype; D006943:Hyperglycemia / Q000503:physiopathology; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D048056:Mitogen-Activated Protein Kinase 9 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011247:Pregnancy; D011254:Pregnancy in Diabetics / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D046509:Tissue Culture Techniques
D000873:Anthracenes; C432165:pyrazolanthrone; D048056:Mitogen-Activated Protein Kinase 9; D048031:JNK Mitogen-Activated Protein Kinases