Transgenic mice overproducing human thioredoxin-1, an antioxidative and anti-apoptotic protein, prevents diabetic embryopathy

Kamimoto, Yuki; Sugiyama, Takashi; Kihira, Tomohisa; Zhang, L.; Murabayashi, Nao; Umekawa, Takashi; Nagao, Kenji; Ma, Ning; Toyoda, Nagayasu; Yodoi, Junji; Sagawa, Norimasa

doi:10.1007/s00125-010-1784-y

Cited by 33 publications

(26 citation statements)

References 43 publications

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“…Maternal diabetes induces 28% NTDs in the C57BL/6J background in our study. This is consistent with the finding from two other groups that maternal hyperglycemia induces more than 22% NTDs (exencephaly) in the C57BL/6J background (19,41). Our current observation also is in line with our previous finding (23,24).…”

Section: Discussionsupporting

confidence: 94%

Trehalose prevents neural tube defects by correcting maternal diabetes-suppressed autophagy and neurogenesis

Xu¹,

Li²,

Wang³

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

114

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isting maternal diabetes increases the risk of neural tube defects (NTDs). The mechanism underlying maternal diabetes-induced NTDs is not totally defined, and its prevention remains a challenge. Autophagy, an intracellular process to degrade dysfunction protein and damaged cellular organelles, regulates cell proliferation, differentiation, and apoptosis. Because autophagy impairment causes NTDs reminiscent of those observed in diabetic pregnancies, we hypothesize that maternal diabetes-induced autophagy impairment causes NTD formation by disrupting cellular homeostasis, leading to endoplasmic reticulum (ER) stress and apoptosis, and that restoration of autophagy by trehalose, a natural disaccharide, prevents diabetes-induced NTDs. Embryos from nondiabetic and type 1 diabetic mice fed with or without 2 or 5% trehalose water were used to assess markers of autophagy, ER stress, and neurogenesis, numbers of autophagosomes, gene expression that regulates autophagy, NTD rates, indices of mitochondrial dysfunction, and neuroepithelial cell apoptosis. Maternal diabetes suppressed autophagy by significantly reducing LC3-II expression, autophagosome numbers, and GFP-LC3 punctate foci in neuroepithelial cells and by altering autophagy-related gene expression. Maternal diabetes delayed neurogenesis by blocking Sox1 neural progenitor differentiation. Trehalose treatment reversed autophagy impairment and prevented NTDs in diabetic pregnancies. Trehalose resolved homeostatic imbalance by correcting mitochondrial defects, dysfunctional proteins, ER stress, apoptosis, and delayed neurogenesis in the neural tubes exposed to hyperglycemia. Our study demonstrates for the first time that maternal diabetes suppresses autophagy in neuroepithelial cells of the developing neural tube, leading to NTD formation, and provides evidence for the potential efficacy of trehalose as an intervention against hyperglycemia-induced NTDs. diabetic embryopathy; autophagy; trehalose; neurogenesis; neural tube defects PREGESTATIONAL DIABETES significantly increases the risk of neural tube defects (NTDs), also known as diabetic embryopathy. There are three to 10 times more NTDs in the offspring of diabetic mothers than in those of nondiabetic mothers (3, 9, 36). Because optimal glycemic control is difficult to achieve and maintain, and even transient exposure to diabetes causes NTDs, maternal diabetes-induced NTDs are significant health problems for both the mother and child. The seriousness of these relationships is emphasized by the upsurge in diabetic pregnancies; nearly 3 million American women and 70 million women worldwide of reproductive age (18 -44 yr) have diabetes today, and this number is expected double by 2030. Although diabetic mellitus is a complex metabolic disease, hyperglycemia is the sole mediator of diabetes teratogenicity. Indeed, clinical studies have revealed a strong correlation between the degree of maternal hyperglycemia and the rate and severity of birth defects (15, 29). When whole rodent embryos are cultured in high concentra...

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Section: Discussionsupporting

confidence: 94%

Trehalose prevents neural tube defects by correcting maternal diabetes-suppressed autophagy and neurogenesis

Xu¹,

Li²,

Wang³

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

114

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“…Here, we used a mouse model of streptozotocin (STZ)–induced diabetes to induce sustained maternal hyperglycemia (glucose, >250 mg/dl). In our studies (11, 39) and those of others (35, 40), this mouse model on a C57BL/6J background has consistently produced an incidence rate of more than 22% in embryos exposed to hyperglycemia. In contrast, embryos from nondiabetic control mice display a rate of 0 to 1% NTDs.…”

Section: Discussionsupporting

confidence: 77%

“…We (4, 12) and others (19, 35, 40) have used a rodent model of STZ-induced diabetes in research of diabetic embryopathy. Briefly, 6- to 8-week-old mice were intravenously injected daily with STZ (75 mg/kg) in the tail vein over 2 days to induce diabetes.…”

Section: Methodsmentioning

confidence: 99%

Maternal Hyperglycemia Activates an ASK1–FoxO3a–Caspase 8 Pathway That Leads to Embryonic Neural Tube Defects

Yang

et al. 2013

Sci. Signal.

196

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Neural tube defects result from failure to completely close neural tubes during development. Maternal diabetes is a substantial risk factor for neural tube defects, and available evidence suggests that the mechanism that links hyperglycemia to neural tube defects involves oxidative stress and apoptosis. We demonstrated that maternal hyperglycemia correlated with activation of the apoptosis signal–regulating kinase 1 (ASK1) in the developing neural tube, and Ask1 gene deletion was associated with reduced neuroepithelial cell apoptosis and development of neural tube defects. ASK1 activation stimulated the activity of the transcription factor FoxO3a, which increased the abundance of the apoptosis-promoting adaptor protein TRADD, leading to activation of caspase 8. Hyperglycemia-induced apoptosis and the development of neural tube defects were reduced with genetic ablation of either FoxO3a or Casp8 or inhibition of ASK1 by thioredoxin. Examination of human neural tissues affected by neural tube defects revealed increased activation or abundance of ASK1, FoxO3a, TRADD, and caspase 8. Thus, activation of an ASK1–FoxO3a–TRADD–caspase 8 pathway participates in the development of neural tube defects, which could be prevented by inhibiting intermediates in this cascade.

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“…We11121327 and others606162 have used a rodent model of Streptozotocin (STZ)-induced diabetes in research of diabetic embryopathy. Briefly, 8- to 10-week old female mice were intravenously injected daily with 75 mg kg −1 STZ in the tail vein over 2 days to induce diabetes.…”

Section: Methodsmentioning

confidence: 99%

Protein kinase C-alpha suppresses autophagy and induces neural tube defects via miR-129-2 in diabetic pregnancy

Wang

Reece

et al. 2017

Nat Commun

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Gene deletion-induced autophagy deficiency leads to neural tube defects (NTDs), similar to those in diabetic pregnancy. Here we report the key autophagy regulators modulated by diabetes in the murine developing neuroepithelium. Diabetes predominantly leads to exencephaly, induces neuroepithelial cell apoptosis and suppresses autophagy in the forebrain and midbrain of NTD embryos. Deleting the Prkca gene, which encodes PKCα, reverses diabetes-induced autophagy impairment, cellular organelle stress and apoptosis, leading to an NTD reduction. PKCα increases the expression of miR-129-2, which is a negative regulator of autophagy. miR-129-2 represses autophagy by directly targeting PGC-1α, a positive regulator for mitochondrial function, which is disturbed by maternal diabetes. PGC-1α supports neurulation by stimulating autophagy in neuroepithelial cells. These findings identify two negative autophagy regulators, PKCα and miR-129-2, which mediate the teratogenicity of hyperglycaemia leading to NTDs. We also reveal a function for PGC-1α in embryonic development through promoting autophagy and ameliorating hyperglycaemia-induced NTDs.

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Transgenic mice overproducing human thioredoxin-1, an antioxidative and anti-apoptotic protein, prevents diabetic embryopathy

Cited by 33 publications

References 43 publications

Trehalose prevents neural tube defects by correcting maternal diabetes-suppressed autophagy and neurogenesis

Trehalose prevents neural tube defects by correcting maternal diabetes-suppressed autophagy and neurogenesis

Maternal Hyperglycemia Activates an ASK1–FoxO3a–Caspase 8 Pathway That Leads to Embryonic Neural Tube Defects

Protein kinase C-alpha suppresses autophagy and induces neural tube defects via miR-129-2 in diabetic pregnancy

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