Peroxynitrites and impaired modulation of nitric oxide concentrations in embryos from diabetic rats during early organogenesis

Jawerbaum, Alicia; Higa, Romina; White, Verónica; Capobianco, Evangelina; Pustovrh, María Carolina; Sinner, Débora; Martínez, Nora; González, Ezequiel

doi:10.1530/rep.1.00699

Cited by 36 publications

(34 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In Alx3 -deficient embryonic cells, excess oxidative stress is a consequence of increased production of ROS, as well as of reactive nitrogen species evidenced by elevated nitrotyrosine content and expression of inducible NOS, which has been implicated in the pathogenesis of embryonic malformations induced by maternal diabetes 43, 55 .…”

Section: Discussionmentioning

confidence: 99%

Embryonic defence mechanisms against glucose-dependent oxidative stress require enhanced expression of Alx3 to prevent malformations during diabetic pregnancy

García‐Sanz

Mirasierra

Moratalla

et al. 2017

Sci Rep

View full text Add to dashboard Cite

Oxidative stress constitutes a major cause for increased risk of congenital malformations associated to severe hyperglycaemia during pregnancy. Mutations in the gene encoding the transcription factor ALX3 cause congenital craniofacial and neural tube defects. Since oxidative stress and lack of ALX3 favour excessive embryonic apoptosis, we investigated whether ALX3-deficiency further increases the risk of embryonic damage during gestational hyperglycaemia in mice. We found that congenital malformations associated to ALX3-deficiency are enhanced in diabetic pregnancies. Increased expression of genes encoding oxidative stress-scavenging enzymes in embryos from diabetic mothers was blunted in the absence of ALX3, leading to increased oxidative stress. Levels of ALX3 increased in response to glucose, but ALX3 did not activate oxidative stress defence genes directly. Instead, ALX3 stimulated the transcription of Foxo1, a master regulator of oxidative stress-scavenging genes, by binding to a newly identified binding site located in the Foxo1 promoter. Our data identify ALX3 as an important component of the defence mechanisms against the occurrence of developmental malformations during diabetic gestations, stimulating the expression of oxidative stress-scavenging genes in a glucose-dependent manner via Foxo1 activation. Thus, ALX3 deficiency provides a novel molecular mechanism for developmental defects arising from maternal hyperglycaemia.

show abstract

Section: Discussionmentioning

confidence: 99%

Embryonic defence mechanisms against glucose-dependent oxidative stress require enhanced expression of Alx3 to prevent malformations during diabetic pregnancy

García‐Sanz

Mirasierra

Moratalla

et al. 2017

Sci Rep

View full text Add to dashboard Cite

show abstract

“…Although nitric oxide is a weak free radical, its oxidant properties are enhanced when nitric oxide reacts with a superoxide to form peroxynitrite [22]. Jawerbaum et al reported that intense nitrotyrosine immunostaining indicative of peroxynitrite was detected in the neural tube and neural folds of embryos of diabetic rats [23]. These findings suggest that increased expression of iNOS in diabetic embryos results in an excess of nitric oxide, which then leads to peroxynitrite accumulation.…”

Section: Discussionmentioning

confidence: 99%

“…Nitric oxide reacts with superoxide to form the powerful oxidant, peroxynitrite (ONOO − ), which is thought to play a role in nitric oxidedependent cytotoxicity [22]. It has been reported that NOS activity and nitric oxide levels are elevated and that peroxynitrite is formed in the maldeveloped neural tube of embryos of diabetic dams [23]. Based on these findings, we hypothesised that maternal hyperglycaemia might induce iNOS expression in the neural tube of embryos and that the overproduction of nitric oxide is involved in diabetic embryopathy.…”

Section: Introductionmentioning

confidence: 99%

Prevention of neural tube defects by loss of function of inducible nitric oxide synthase in fetuses of a mouse model of streptozotocin-induced diabetes

et al. 2009

View full text Add to dashboard Cite

Aims/hypothesis Maternal diabetes during pregnancy increases the risk of congenital malformations such as neural tube defects (NTDs). Although the mechanism of this effect is uncertain, it is known that levels of nitric oxide synthase (NOS) and nitric oxide are elevated in embryos of a mouse model of diabetes. We postulated that overproduction of nitric oxide causes diabetes-induced congenital malformations and that inhibition of inducible NOS (iNOS) might prevent diabetic embryopathy. Methods Mice were rendered hyperglycaemic by intraperitoneal injection of streptozotocin. The incidence of congenital malformations including NTDs was evaluated on gestational day 18.5. We assessed the involvement of iNOS in diabetesinduced malformation by administering ONO-1714, a specific inhibitor of iNOS, to pregnant mice with streptozotocininduced diabetic mice and by screening mice with iNOS deficiency due to genetic knockout (iNos −/− ). Results ONO-1714 markedly reduced the incidence of congenital anomalies, including NTDs, in fetuses of a mouse model of diabetes. It also prevented apoptosis in the head region of fetuses, indicating that iNOS is involved in diabetesrelated congenital malformations. Indeed, no NTDs were observed in fetuses of diabetic iNos −/− mice and the incidence of other malformations was also markedly reduced. Conclusions/interpretation We conclude that increased iNOS activity during organogenesis plays a crucial role in the pathogenesis of diabetes-induced malformations and suggest that inhibitors of iNOS might help prevent malformations, especially NTDs, in diabetic pregnancy.

show abstract

“…Elevated NO may directly interact with ROS generated under hyperglycemic conditions to form potent oxidant peroxynitrite leading to nitrosative stress 40, 41 (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

Advances in revealing the molecular targets downstream of oxidative stress–induced proapoptotic kinase signaling in diabetic embryopathy

Wang

Reece

Yang

2015

American Journal of Obstetrics and Gynecology

View full text Add to dashboard Cite

Pre-existing maternal diabetes is a high risk factor of diabetic embryopathy, such as neural tube defects (NTDs) and congenital heart defects (CHD). Maternal diabetes significantly increases the production of reactive oxygen species (ROS) resulting in oxidative stress and diabetic embryopathy. Multiple cellular and metabolic factors contribute to these processes. FoxO3a has been demonstrated as a key transcription factor in the signaling transduction pathways responsible for maternal diabetes-induced birth defects. ASK1 activated by oxidative stress stimulates nuclear translocation of FoxO3a, resulting in over-expression of TRADD, which, in turn, leads to caspase 8 activation and apoptosis. Maternal diabetes-activated JNK1/2, downstream effectors of ASK1, can be blocked by SOD1 overexpression, suggesting that oxidative stress is responsible for JNK1/2 signaling activation. Deletion of JNK1/2 significantly suppressed the activity of FoxO3a. These obersvations indicate that maternal diabetes-induced oxidative stress stimulates the activation of ASK1, JNK1/2, FoxO3a, TRADD, caspase 8 cleavage, finally, apoptosis and diabetic embryopathy.

show abstract

Peroxynitrites and impaired modulation of nitric oxide concentrations in embryos from diabetic rats during early organogenesis

Cited by 36 publications

References 52 publications

Embryonic defence mechanisms against glucose-dependent oxidative stress require enhanced expression of Alx3 to prevent malformations during diabetic pregnancy

Embryonic defence mechanisms against glucose-dependent oxidative stress require enhanced expression of Alx3 to prevent malformations during diabetic pregnancy

Prevention of neural tube defects by loss of function of inducible nitric oxide synthase in fetuses of a mouse model of streptozotocin-induced diabetes

Advances in revealing the molecular targets downstream of oxidative stress–induced proapoptotic kinase signaling in diabetic embryopathy

Contact Info

Product

Resources

About