» Articles » PMID: 22961085

C-Jun NH2-terminal Kinase 1/2 and Endoplasmic Reticulum Stress As Interdependent and Reciprocal Causation in Diabetic Embryopathy

Overview
Journal Diabetes
Specialty Endocrinology
Date 2012 Sep 11
PMID 22961085
Citations 55
Authors
Affiliations
Soon will be listed here.
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.

Citing Articles

Hypertensive disorders of pregnancy affected thyroid hormone synthesis via endoplasmic reticulum stress in preterm infant rats.

Sun M, Wu C, Jiang J, He Y, Zhu S, Yu Y Heliyon. 2025; 11(1):e41021.

PMID: 39790871 PMC: 11714400. DOI: 10.1016/j.heliyon.2024.e41021.


GLCCI1 alleviates GRP78-initiated endoplasmic reticulum stress-induced apoptosis of retinal ganglion cells in diabetic retinopathy by upregulating and interacting with HSP90AB1.

Liu J, Yu H, Yu S, Liu M, Chen X, Wang Y Sci Rep. 2024; 14(1):26665.

PMID: 39496608 PMC: 11535184. DOI: 10.1038/s41598-024-75874-4.


Embryonic diapause due to high glucose is related to changes in glycolysis and oxidative phosphorylation, as well as abnormalities in the TCA cycle and amino acid metabolism.

Hong J, Tong H, Wang X, Lv X, He L, Yang X Front Endocrinol (Lausanne). 2024; 14:1135837.

PMID: 38170036 PMC: 10759208. DOI: 10.3389/fendo.2023.1135837.


MicroRNA-322 overexpression reduces neural tube defects in diabetic pregnancies.

Wang G, Song S, Shen W, Reece E, Yang P Am J Obstet Gynecol. 2023; 230(2):254.e1-254.e13.

PMID: 37531989 PMC: 10828117. DOI: 10.1016/j.ajog.2023.07.048.


4-PBA Attenuates Fat Accumulation in Cultured Spotted Seabass Fed High-Fat-Diet via Regulating Endoplasmic Reticulum Stress.

Xia T, Liao Y, Li L, Sun L, Ding N, Wu Y Metabolites. 2022; 12(12).

PMID: 36557235 PMC: 9784988. DOI: 10.3390/metabo12121197.


References
1.
Yang P, Zhao Z, Reece E . Blockade of c-Jun N-terminal kinase activation abrogates hyperglycemia-induced yolk sac vasculopathy in vitro. Am J Obstet Gynecol. 2008; 198(3):321.e1-7. DOI: 10.1016/j.ajog.2007.09.010. View

2.
Yang P, Zhao Z, Reece E . Involvement of c-Jun N-terminal kinases activation in diabetic embryopathy. Biochem Biophys Res Commun. 2007; 357(3):749-54. DOI: 10.1016/j.bbrc.2007.04.023. View

3.
Sun F, Kawasaki E, Akazawa S, Hishikawa Y, Sugahara K, Kamihira S . Apoptosis and its pathway in early post-implantation embryos of diabetic rats. Diabetes Res Clin Pract. 2005; 67(2):110-8. DOI: 10.1016/j.diabres.2004.06.008. View

4.
Reece E, Pinter E, Leranth C, Sanyal M, Hobbins J, Mahoney M . Ultrastructural analysis of malformations of the embryonic neural axis induced by in vitro hyperglycemic conditions. Teratology. 1985; 32(3):363-73. DOI: 10.1002/tera.1420320306. View

5.
Pugazhenthi S, Nesterova A, Jambal P, Audesirk G, Kern M, Cabell L . Oxidative stress-mediated down-regulation of bcl-2 promoter in hippocampal neurons. J Neurochem. 2003; 84(5):982-96. DOI: 10.1046/j.1471-4159.2003.01606.x. View