Hyperglycemia Induces Cellular Hypoxia through Production of Mitochondrial ROS Followed by Suppression of Aquaporin-1

Sada, Kiminori; Nishikawa, Takeshi; Kukidome, Daisuke; Yoshinaga, Tomoaki; Kajihara, Nobuhiro; Sonoda, Kazuhiro; Senokuchi, Takafumi; Motoshima, Hiroyuki; Matsumura, Takeshi; Araki, Eiichi

doi:10.1371/journal.pone.0158619

Cited by 91 publications

(62 citation statements)

References 22 publications

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“…Progressive hyperglycemia and hyperlipidemia are common (ACOG Practice Bulletin No : Obesity in Pregnancy”,; Retnakaran et al, ). Immune activation leads to a chronic state of low‐grade systemic inflammation (Bremer, Devaraj, Afify, & Jialal, ), stimulation of the transcription factor nuclear factor kappa B (NFkB) pathway (Shi et al, ) and cellular damage associated with oxidative stress (Brownlee, ; Sada et al, ). The role of maternal–fetal immune dysfunction in the development of neurobehavioral impairment has numerous strong lines of supporting evidence reviewed elsewhere (Meltzer & Van de Water, ).…”

Section: Discussionmentioning

confidence: 99%

Adiposity and weight gain during pregnancy associate independently with behavior of infant rhesus monkeys (Macaca mulatta)

Walker

VandeVoort

et al. 2018

Developmental Psychobiology

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Growing evidence identifies maternal adiposity as a potentially modifiable risk factor for adverse neurodevelopment. This retrospective cohort analysis examined whether maternal prepregnancy adiposity and gestational weight gain were associated with behavioral outcomes in 173 rhesus macaque infants at the California National Primate Research Center. Dams conceived indoors, had uncomplicated pregnancies, delivered vaginally, and reared infants indoors. Infants underwent standardized biobehavioral analysis at 90-120 days of age from 3/2001-5/2015. Offspring of mothers with greater baseline adiposity or gestational weight gain exhibited a pattern of poor adaptability characterized by greater emotionality as the assessments proceeded, blunted affective response to a human intruder challenge, and reduced interest in novel stimuli which is associated with poorer social functioning later in life. They also had lower cortisol levels following dexamethasone suppression, perhaps a response to cortisol excess during gestation. These results amplify growing public health concerns implicating maternal adiposity in impaired fetal neurobehavioral programming.

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Section: Discussionmentioning

confidence: 99%

Adiposity and weight gain during pregnancy associate independently with behavior of infant rhesus monkeys (Macaca mulatta)

Walker

VandeVoort

et al. 2018

Developmental Psychobiology

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“…These modifications include enhanced non-enzymatic glycation, sorbitol-myo-inositol-mediated changes, redox potential alterations, and the activation of protein kinase C (PKC) [23]. Hyperglycemia also causes an increase in reactive oxygen species (ROS) in endothelial cells, overwhelming the cell's ability to overcome oxidative stress [24,25]. In the following section, we will discuss the effects of diabetes on the vascular endothelium and how they may potentially play a role in the development of diabetic cardiomyopathy.…”

Section: Potential Mechanisms Underlying Diabetic Cardiomyopathymentioning

confidence: 99%

Vascular endothelial dysfunction, a major mediator in diabetic cardiomyopathy

2018

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Diabetes mellitus is currently a major public health problem. A common complication of diabetes is cardiac dysfunction, which is recognized as a microvascular disease that leads to morbidity and mortality in diabetic patients. While ischemic events are commonly observed in diabetic patients, the risk for developing heart failure is also increased, independent of the severity of coronary artery disease and hypertension. This diabetes-associated clinical entity is considered a distinct disease process referred to as "diabetic cardiomyopathy". However, it is not clear how diabetes promotes cardiac dysfunction. Vascular endothelial dysfunction is thought to be one of the key risk factors. The impact of diabetes on the endothelium involves several alterations, including hyperglycemia, fatty acid oxidation, reduced nitric oxide (NO), oxidative stress, inflammatory activation, and altered barrier function. The current review provides an update on mechanisms that specifically target endothelial dysfunction, which may lead to diabetic cardiomyopathy.

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“…hours and subsequently only at 48 hours. These timepoints correlate well with studies that link ROS overproduction with decreased cell viability or proliferation [65,79,85] [84,97]. Rather than investing in cost-prohibitive incubation equipment, fixating samples immediately following high glucose treatments and using an antibody-based stain could be used to identify oxidative stress and ROS production.…”

Section: Challenges and Limitationssupporting

confidence: 70%

Evaluation of Endothelial Cell Responses to Elevated Glucose

Sugerman¹

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Developing a tissue-engineered Blood Vessel Mimic (BVM) to represent diabetic macrovascular disease could expedite design of new vascular devices specifically tailored to diabetic patients. In contribution toward this model, this thesis assessed Human Umbilical Vein Endothelial Cell (HUVEC) responses to high glucose conditions. Interleukin 6 (IL-6) and Cluster of Differentiation 36 (CD36) were selected to signify oxidative stress activity, a hallmark of diabetic macrovascular disease. Next, activity of potential reference genes B2M, HPRT1, and ACTB was assessed. All genes were found to exceed acceptable variability, so the E-ΔC T method of data analysis was selected. Next, cellular responses to high glucose treatment at 10.5 mM glucose and 25.5 mM glucose for 7 and 14 days were measured by qPCR. IL-6 mRNA expression increased significantly (p<0.001) following treatment with 25.5 mM glucose at both timepoints. Finally, fluorescent staining for Reactive Oxygen Species (ROS) production and cell viability was performed on HUVECs treated with 10.5-and 25.5-mM glucose for 24 and 48 hours. No differences in ROS production or cell viability were detected due to uncontrolled cell damage during the two-hour staining and imaging procedure. This thesis was limited by low reaction efficiency in qPCR reactions due to mistaken purchasing of primers with included probe-quencher reporters. Measurement of reaction efficiency facilitated valid analysis of data collected using these primers. Imaging experiments were unsuccessful due to a lack of incubation equipment designated for cells undergoing live staining and imaging. Alternative imaging assessments of oxidative stress activity were proposed to circumvent this problem. v ACKNOWLEDGMENTS I would like to thank Dr. Kristen Cardinal for her guidance and support throughout my pursuit of a Master of Science degree. The privilege of working with Dr. Cardinal has inspired my curiosity, determination, and enduring love of research. Her positive impact on all of her students-especially those in her research laboratory-inspires greatness in our department.

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Hyperglycemia Induces Cellular Hypoxia through Production of Mitochondrial ROS Followed by Suppression of Aquaporin-1

Cited by 91 publications

References 22 publications

Adiposity and weight gain during pregnancy associate independently with behavior of infant rhesus monkeys (Macaca mulatta)

Adiposity and weight gain during pregnancy associate independently with behavior of infant rhesus monkeys (Macaca mulatta)

Vascular endothelial dysfunction, a major mediator in diabetic cardiomyopathy

Evaluation of Endothelial Cell Responses to Elevated Glucose

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