title: c-Jun NH2-terminal kinase 1/2 and endoplasmic reticulum stress as interdependent and reciprocal causation in diabetic embryopathy.
abstract: Embryos exposed to high glucose exhibit aberrant maturational and cytoarchitectural cellular changes, implicating cellular organelle stress in diabetic embryopathy. c-Jun-N-terminal kinase 1/2 (JNK1/2) activation is a causal event in maternal diabetes-induced neural tube defects (NTD). However, the relationship between JNK1/2 activation and endoplasmic reticulum (ER) stress in diabetic embryopathy has never been explored. We found that maternal diabetes significantly increased ER stress markers and induced swollen/enlarged ER lumens in embryonic neuroepithelial cells during neurulation. Deletion of either jnk1 or jnk2 gene diminished hyperglycemia-increased ER stress markers and ER chaperone gene expression. In embryos cultured under high-glucose conditions (20 mmol/L), the use of 4-phenylbutyric acid (4-PBA), an ER chemical chaperone, diminished ER stress markers and abolished the activation of JNK1/2 and its downstream transcription factors, caspase 3 and caspase 8, and Sox1 neural progenitor apoptosis. Consequently, both 1 and 2 mmol/L 4-PBA significantly ameliorated high glucose-induced NTD. We conclude that hyperglycemia induces ER stress, which is responsible for the proapoptotic JNK1/2 pathway activation, apoptosis, and NTD induction. Suppressing JNK1/2 activation by either jnk1 or jnk2 gene deletion prevents ER stress. Thus, our study reveals a reciprocal causation of ER stress and JNK1/2 in mediating the teratogenicity of maternal diabetes.
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Xuezheng
authors.initials: X
authors.lastname: Li
authors.forename: Cheng
authors.initials: C
authors.lastname: Xu
authors.forename: Peixin
authors.initials: P
authors.lastname: Yang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D015415:Biomarkers / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology* / Q000235:genetics; D059865:Endoplasmic Reticulum Stress; D005260:Female; D005315:Fetal Diseases / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D017353:Gene Deletion; D006943:Hyperglycemia / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D048055:Mitogen-Activated Protein Kinase 8 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D048056:Mitogen-Activated Protein Kinase 9 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018832:Molecular Chaperones / Q000096:biosynthesis; D009436:Neural Tube Defects / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control*; D046569:Neuroepithelial Cells / Q000187:drug effects / Q000378:metabolism; D054261:Neurulation / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D010654:Phenylbutyrates / Q000494:pharmacology; D011247:Pregnancy; D011254:Pregnancy in Diabetics / Q000201:enzymology*; D055748:SOXB1 Transcription Factors / Q000378:metabolism
chemical_list: D015415:Biomarkers; D018832:Molecular Chaperones; D010654:Phenylbutyrates; D055748:SOXB1 Transcription Factors; C098693:Sox1 protein, mouse; C075773:4-phenylbutyric acid; D048056:Mitogen-Activated Protein Kinase 9; D048055:Mitogen-Activated Protein Kinase 8; C505409:Casp3 protein, mouse; C505526:Casp8 protein, mouse; D053148:Caspase 3; D053181:Caspase 8