Oxidative stress-induced JNK1/2 activation triggers proapoptotic signaling and apoptosis that leads to diabetic embryopathy.
Oxidative stress and apoptosis are implicated in the pathogenesis of diabetic embryopathy. The proapoptotic c-Jun NH(2)-terminal kinases (JNK)1/2 activation is associated with diabetic embryopathy. We sought to determine whether 1) hyperglycemia-induced oxidative stress is responsible for the activation of JNK1/2 signaling, 2) JNK1 contributes to the teratogenicity of hyperglycemia, and 3) both JNK1 and JNK2 activation cause activation of downstream transcription factors, caspase activation, and apoptosis, resulting in neural tube defects (NTDs). Wild-type (WT) embryos from nondiabetic WT dams and WT, superoxide dismutase (SOD)1-overexpressing, jnk1(+/-), jnk1(-/-), and jnk2(-/-) embryos exposed to maternal hyperglycemia were used to assess JNK1/2 activation, NTDs, activation of transcription factors downstream of JNK1/2, caspase cascade, and apoptosis. SOD1 overexpression abolished diabetes-induced activation of JNK1/2 and their downstream effectors: phosphorylation of c-Jun, activating transcription factor 2, and E twenty-six-like transcription factor 1 and dephosphorylation of forkhead box class O3a. jnk1(-/-) embryos had significantly lower incidences of NTDs than those of WT or jnk1(+/-) embryos. Either jnk1 or jnk2 gene deletion blocked diabetes-induced activation of JNK1/2 signaling, caspases 3 and 8, and apoptosis in Sox1(+) neural progenitors of the developing neural tube. Our results show that JNK1 and JNK2 are equally involved in diabetic embryopathy and that the oxidative stress-JNK1/2-caspase pathway mediates the proapoptotic signals and the teratogenicity of maternal diabetes.
Department of Obstetrics, Gynecology & Reproductive Sciences, University of Maryland School of Medicine, Baltimore, Maryland, USA.
Xuezheng
X
Li
Hongbo
H
Weng
Cheng
C
Xu
E Albert
EA
Reece
Peixin
P
Yang
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D020169:Caspases / Q000378:metabolism; D003920:Diabetes Mellitus / Q000503:physiopathology*; D004789:Enzyme Activation; D005260:Female; D005315:Fetal Diseases / Q000209:etiology*; D017353:Gene Deletion; D006943:Hyperglycemia / Q000503:physiopathology; D048688:MAP Kinase Kinase 7 / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D048055:Mitogen-Activated Protein Kinase 8 / Q000235:genetics; D048056:Mitogen-Activated Protein Kinase 9 / Q000172:deficiency; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009436:Neural Tube Defects / Q000209:etiology; D018384:Oxidative Stress / Q000502:physiology*; D011247:Pregnancy; D011248:Pregnancy Complications / Q000209:etiology; D013482:Superoxide Dismutase / Q000096:biosynthesis; D000072105:Superoxide Dismutase-1
D048868:Adaptor Proteins, Signal Transducing; C403619:Mapk8ip3 protein, mouse; D009419:Nerve Tissue Proteins; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D048056:Mitogen-Activated Protein Kinase 9; D048055:Mitogen-Activated Protein Kinase 8; D048688:MAP Kinase Kinase 7; D020169:Caspases