The role of NOX enzymes in ethanol-induced oxidative stress and apoptosis in mouse embryos

Dong, Jian; Sulik, Kathleen K.; Chen, Shao Yu

doi:10.1016/j.toxlet.2009.12.012

Cited by 121 publications

(91 citation statements)

References 54 publications

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“…ROS-generating NADPH oxidases play a dual role in regulating cellular apoptosis (8,(51)(52)(53). NADPH-generated ROS play an important role in ethanol-induced apoptosis (51).…”

Section: Discussionmentioning

confidence: 99%

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AMP-activated Protein Kinase (AMPK) Negatively Regulates Nox4-dependent Activation of p53 and Epithelial Cell Apoptosis in Diabetes

Eid

Ford

Block

et al. 2010

Journal of Biological Chemistry

230

260

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Diabetes and high glucose (HG) increase the generation of NADPH oxidase-derived reactive oxygen species and induce apoptosis of glomerular epithelial cells (podocytes). Loss of podocytes contributes to albuminuria, a major risk factor for progression of kidney disease. Here, we show that HG inactivates AMP-activated protein kinase (AMPK), up-regulates Nox4, enhances NADPH oxidase activity, and induces podocyte apoptosis. Activation of AMPK blocked HG-induced expression of Nox4, NADPH oxidase activity, and apoptosis. We also identified the tumor suppressor protein p53 as a mediator of podocyte apoptosis in cells exposed to HG. Inactivation of AMPK by HG up-regulated the expression and phosphorylation of p53, and p53 acted downstream of Nox4. To investigate the mechanism of podocyte apoptosis in vivo, we used OVE26 mice, a model of type 1 diabetes. Glomeruli isolated from these mice showed decreased phosphorylation of AMPK and enhanced expression of Nox4 and p53. Pharmacologic activation of AMPK by 5-aminoimidazole-4-carboxamide-1-riboside in OVE26 mice attenuated Nox4 and p53 expression. Administration of 5-aminoimidazole-4-carboxamide-1-riboside also prevented renal hypertrophy, glomerular basement thickening, foot process effacement, and podocyte loss, resulting in marked reduction in albuminuria. Our results uncover a novel function of AMPK that integrates metabolic input to Nox4 and provide new insight for activation of p53 to induce podocyte apoptosis. The data indicate the potential therapeutic utility of AMPK activators to block Nox4 and reactive oxygen species generation and to reduce urinary albumin excretion in type 1 diabetes.One of the major early features of diabetic kidney disease is injury to glomerular epithelial cells or podocytes, which contribute to the increased urinary albumin losses and accelerated sclerosis of the glomerular microvascular bed (1). Podocyte injury manifests as phenotypic changes that range from foot process effacement and altered localization or abundance of specific slit diaphragm proteins to frank apoptosis with detachment of the cells from the glomerular basement membrane (GBM) 2 with decreased cell density (2-4). The mechanism(s) of podocyte depletion in diabetes are poorly understood.Expression of antioxidant enzymes in some animal models ameliorates diabetic kidney disease, thus establishing a role of reactive oxygen species (ROS) (5, 6). More recently, along with ROS generated from mitochondrial respiratory chains, NADPH oxidase-derived ROS have been shown to play a significant role in injury to various organs, including the kidney (2, 7). A number of homologs of the phagocyte NADPH oxidase catalytic subunit (Nox2) have been identified. These enzymes participate in a number of biological processes, including proliferation, migration, contraction, cytoskeletal organization, fibrosis, and apoptosis (8). Along with Nox2, Nox1 and Nox4 are abundantly expressed in the renal cortex (9). We showed that Nox4 is expressed in rat and mouse glomeruli and contributes to matrix ac...

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“…ROS-generating NADPH oxidases play a dual role in regulating cellular apoptosis (8,(51)(52)(53). NADPH-generated ROS play an important role in ethanol-induced apoptosis (51).…”

Section: Discussionmentioning

confidence: 99%

“…NADPH-generated ROS play an important role in ethanol-induced apoptosis (51). However, NADPH oxidase-derived ROS, including Nox4, inhibit apoptosis in pancreatic cancer cells (52,53).…”

Section: Discussionmentioning

confidence: 99%

AMP-activated Protein Kinase (AMPK) Negatively Regulates Nox4-dependent Activation of p53 and Epithelial Cell Apoptosis in Diabetes

Eid

Ford

Block

et al. 2010

Journal of Biological Chemistry

230

260

View full text Add to dashboard Cite

show abstract

“…The involvement of oxidative stress in FASD is well established in the literature [40,41,42]. Even a brief exposure to ethanol during gestation can produce an imbalance in the brain's intracellular redox state [43]. Such imbalances correlate with FASD-relevant spatial learning deficits [44].…”

Section: Discussionmentioning

confidence: 99%

Molecular Changes during Neurodevelopment following Second-Trimester Binge Ethanol Exposure in a Mouse Model of Fetal Alcohol Spectrum Disorder: From Immediate Effects to Long-Term Adaptation

Mantha

Laufer

Singh³

2014

Dev Neurosci

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Fetal alcohol spectrum disorder (FASD) is an umbrella term that refers to a wide range of behavioral and cognitive deficits resulting from prenatal alcohol exposure. It involves changes in brain gene expression that underlie lifelong FASD symptoms. How these changes are achieved from immediate to long-term effects, and how they are maintained, is unknown. We have used the C57BL/6J mouse to assess the dynamics of genomic alterations following binge alcohol exposure. Ethanol-exposed fetal (short-term effect) and adult (long-term effect) brains were assessed for gene expression and microRNA (miRNA) changes using Affymetrix mouse arrays. We identified 48 and 68 differentially expressed genes in short- and long-term groups, respectively. No gene was common between the 2 groups. Short-term (immediate) genes were involved in cellular compromise and apoptosis, which represent ethanol's toxic effects. Long-term genes were involved in various cellular functions, including epigenetics. Using quantitative RT-PCR, we confirmed the downregulation of long-term genes: Camk1g, Ccdc6, Egr3, Hspa5, and Xbp1. miRNA arrays identified 20 differentially expressed miRNAs, one of which (miR-302c) was confirmed. miR-302c was involved in an inverse relationship with Ccdc6. A network-based model involving altered genes illustrates the importance of cellular redox, stress and inflammation in FASD. Our results also support a critical role of apoptosis in FASD, and the potential involvement of miRNAs in the adaptation of gene expression following prenatal ethanol exposure. The ultimate molecular footprint involves inflammatory disease, neurological disease and skeletal and muscular disorders as major alterations in FASD. At the cellular level, these processes represent abnormalities in redox, stress and inflammation, with potential underpinnings to anxiety.

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“…Oxidative stress is an important contributing factor in the pathogenesis of ethanol-induced birth defects Chen and Sulik, 1996;Dong et al, 2010;Kotch et al, 1995). This suggests that therapeutic strategies directed against ROS might be particularly valuable for the prevention of the ethanol-induced damage and malformations in early embryos, in which ROS are involved and the antioxidant capabilities are minimal.…”

Section: Figurementioning

confidence: 99%

Sulforaphane protects against ethanol‐induced oxidative stress and apoptosis in neural crest cells by the induction of Nrf2‐mediated antioxidant response

Chen

Liu

2013

British J Pharmacology

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BACKGROUND AND PURPOSENuclear factor erythroid 2-related factor (Nrf2) is a transcription factor that up-regulates a diverse array of antioxidant genes and protects cells from oxidative damage. This study is designed to determine whether D-L-sulforaphane (SFN) can protect neural crest cells (NCCs), an ethanol-sensitive cell population implicated in fetal alcohol spectrum disorders, against ethanolinduced apoptosis and whether protective effects of SFN are mediated by the induction of Nrf2-mediated antioxidant response. EXPERIMENTAL APPROACHControl, SFN-treated or Nrf2-siRNA transfected NCCs were exposed to ethanol. Nrf2 activation, the expression and activities of Nrf2 downstream antioxidant proteins, reactive oxygen species generation and apoptosis were determined in control and ethanol-exposed NCCs. KEY RESULTSExposure of NCCs to SFN alone significantly increased Nrf2 activation and the expression of Nrf2 downstream antioxidants as well as the activities of the antioxidant enzymes. Treatment of NCCs with SFN along with ethanol significantly decreased ethanol-induced oxidative stress and apoptosis. In contrast, knockdown of Nrf2 by siRNA significantly increased the sensitivity of NCCs to ethanol-induced oxidative stress and apoptosis. Suppression of Nrf2 signalling in NCCs also significantly diminished SFN-mediated antioxidant response and abolished the protective effects of SFN on ethanol-induced oxidative stress and apoptosis. CONCLUSIONS AND IMPLICATIONSThese results demonstrated that Nrf2-mediated antioxidant response plays an important role in the susceptibility of NCCs to ethanol-induced oxidative stress and apoptosis and that the protection of SFN against ethanol-induced oxidative stress and apoptosis in NCCs is mediated by the induction of Nrf2 signalling. AbbreviationsARE, antioxidant response element; D3T, 3H-1,2-dithiole-3-thione; DCHFDA, 2′,7′-dichlorodihydrofluoroscein diacetate; FASD, fetal alcohol spectrum disorder; MTS, 3-(4, 5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium salt; NCC, neural crest cell; NQO1, NAD(P)H:quinone oxidoreductase 1; Nrf2, nuclear factor erythroid 2-related factor; ROS, reactive oxygen species; SFN, D-L-sulforaphane; SOD, superoxide dismutase BJP British Journal of Pharmacology

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The role of NOX enzymes in ethanol-induced oxidative stress and apoptosis in mouse embryos

Cited by 121 publications

References 54 publications

AMP-activated Protein Kinase (AMPK) Negatively Regulates Nox4-dependent Activation of p53 and Epithelial Cell Apoptosis in Diabetes

AMP-activated Protein Kinase (AMPK) Negatively Regulates Nox4-dependent Activation of p53 and Epithelial Cell Apoptosis in Diabetes

Molecular Changes during Neurodevelopment following Second-Trimester Binge Ethanol Exposure in a Mouse Model of Fetal Alcohol Spectrum Disorder: From Immediate Effects to Long-Term Adaptation

Sulforaphane protects against ethanol‐induced oxidative stress and apoptosis in neural crest cells by the induction of Nrf2‐mediated antioxidant response

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