Enhanced oxidative stress and accelerated cellular senescence in glucose-6-phosphate dehydrogenase (G6PD)-deficient human fibroblasts

Ho, Hung‐Yao; Cheng, Mei‐Ling; Lu, Fung‐Jou; Chou, Yi-Hung; Stern, Arnold; Liang, Chi-Ming; Chiu, Daniel T.

doi:10.1016/s0891-5849(00)00331-2

Cited by 95 publications

(60 citation statements)

References 36 publications

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“…After a period of rapid proliferation, cell division rates decrease and ultimately cease; the cells then enter a state of senescence that is characterized by an irreversible G 1 growth arrest and functional and morphologic changes (4,17). Senescence of cells also can occur rapidly in response to various physiologic stresses, such as high glucose, oxidative stress (18), DNA-damaging agents, and other metabolic perturbations.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of Connexin 43 Expression by High Glucose Induces Senescence in Glomerular Mesangial Cells

Zhang

Chen

et al. 2006

Journal of the American Society of Nephrology

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Connexin 43 (Cx43) plays an important role in cell differentiation and growth control, but whether it can be regulated by high glucose and whether it can mediate in glomerular mesangial cells (GMC) the phenotype alterations that are induced by high glucose still remain to be explored. In this study, RNA interference and gene transfer techniques were used to knock down and overexpress Cx43 gene in rat GMC to determine the contribution of Cx43 to GMC senescence that was induced by high glucose. The results show that high glucose (30 mM) not only downregulated Cx43 mRNA and protein expression (P < 0.05) but also increased the percentage of senescence-associated ␤-galactosidase (SA-␤-gal) stained cells and expression of p21 cip1 and p27 kip1 (P < 0.05), indicating that high glucose promoted rat GMC senescence. Knocking down Cx43 gene expression significantly increased the percentage of SA-␤-gal stained cells and p27 kip1 and p21 cip1 expression in GMC (P < 0.05), whereas overexpression of Cx43 significantly decreased the percentage of SA-␤-gal stained cells (P < 0.05). These results demonstrate for the first time that downregulation of Cx43 expression by high glucose promotes the senescence of GMC, which may be involved in the pathogenesis of diabetic nephropathy.

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Section: Discussionmentioning

confidence: 99%

Downregulation of Connexin 43 Expression by High Glucose Induces Senescence in Glomerular Mesangial Cells

Zhang

Chen

et al. 2006

Journal of the American Society of Nephrology

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“…Even though the cells have an increased ability to remove damaging peroxides, a decline in G6PD and GSSG reductase limits the cells' ability to convert GSSG to GSH, which may decrease the overall detoxification capacity and eventually result in GSH depletion. The importance of G6PD was demonstrated by the finding that fibroblasts deficient in this activity senesced at a faster rate in culture (26).…”

Section: Discussionmentioning

confidence: 99%

“…For example, overexpression of superoxide dismutase (SOD) and catalase extended the lifespan of Drosophila melanogaster (40). However, treatment of primary cells with ionizing radiation increased the rate of replicative senescence in culture (34,39), and fibroblasts deficient in glucose-6-phosphate dehydrogenase (G6PD), an enzyme required to generate NADPH for the conversion of oxidized glutathione (GSSG) to GSH, also senesce at a faster rate (26).…”

mentioning

confidence: 99%

Endothelial cells maintain a reduced redox environment even as mitochondrial function declines

Carlisle

Rhoads

et al. 2002

American Journal of Physiology-Cell Physiology

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. Endothelial cells maintain a reduced redox environment even as mitochondrial function declines. Am J Physiol Cell Physiol 283: C1675-C1686, 2002. First published August 22, 2002 10.1152/ajpcell.00092.2002 are an endothelial model of replicative senescence. Oxidative stress, possibly due to dysfunctional mitochondria, is believed to play a key role in replicative senescence and atherosclerosis, an age-related vascular disease. In this study, we determined the effect of cell division on genomic instability, mitochondrial function, and redox status in HUVECs that were able to replicate for ϳ60 cumulative population doublings (CPD). After 20 CPD, the nuclear genome deteriorated and the protein content of the cell population increased. This indicated an increase in cell size, which was accompanied by an increase in oxygen consumption, ATP production, and mitochondrial genome copy number and ϳ10% increase in mitochondrial mass. The antioxidant capacity increased, as seen by an increase in reduced glutathione, glutathione peroxidase, GSSG reductase, and glucose-6-phosphate dehydrogenase. However, by CPD 52, the latter two enzymes decreased, as well as the ratio of mitochondrial-to-nuclear genome copies, the mitochondrial mass, and the oxygen consumption per milligram of protein. Our results signify that HUVECs maintain a highly reducing (GSH) environment as they replicate despite genomic instability and loss of mitochondrial function. replicative senescence; glutathione; cell size changes; genomic instability; human umbilical vein endothelial cells HUMAN UMBILICAL VEIN ENDOTHELIAL CELLS (HUVECs) replicate a finite number of times in culture and are an endothelial model of replicative senescence. Reactive oxygen species (ROS) and oxidative damage to DNA (24), protein (7), and lipid (45) increase with age and have been implicated in aging and replicative senescence (19,48). Oxidative stress has also been implicated in atherosclerosis, an age-related vascular disease, and homocysteine, a contributing factor to atherosclerosis that induces oxidative stress, accelerates endothelial senescence in culture (52). Atherosclerosis is hypothesized to be the result of a "response to injury" of the endothelium. The endothelium must constantly respond to changes in the vascular environment and experiences frequent insults from mechanical, hemodynamic, and inflammatory stresses, all of which enhance oxygen free radical production. In response to injury, endothelial cells must replicate to repair blood vessels. Telomere length is shorter in endothelial cells derived from vessels where there is greater hemodynamic stress, and presumably more endothelial cell replication to repair injury, than in cells isolated from areas of lower stress (10). Injury induced by balloon catheter denudation of rabbit carotid arteries has been shown to result in the accumulation of senescent endothelial cells (18). Studies of the endothelium at atherosclerotic lesions (9, 50) and in vessels from elderly people (30, 50) have detected multinucleated cells ...

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“…Therefore, we hypothesized that overexpression of G6PD would enhance eNOS activity. We measured eNOS activity in intact cells in the absence of exogenously added NADPH or BH 4 . Under basal conditions, overexpression of G6PD significantly increased eNOS activity (17 534Ϯ150 (Figure 4).…”

Section: Enos Activity and G6pd Overexpressionmentioning

confidence: 99%

“…2,3 G6PD-deficient fibroblasts manifest premature senescence in vitro owing to increased local production of ROS, 4 and when challenged additionally with hydrogen peroxide (H 2 O 2 ), demonstrate accelerated cell death. 5 Similarly, vascular endothelial cells with deficient G6PD activity exposed to H 2 O 2 generate increased levels of ROS and deplete intracellular GSH stores, 2 an effect that is associated with diminished cell viability.…”

mentioning

confidence: 99%

Glucose-6-Phosphate Dehydrogenase Overexpression Decreases Endothelial Cell Oxidant Stress and Increases Bioavailable Nitric Oxide

Leopold

Zhang

Scribner

et al. 2003

ATVB

185

145

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Objective-Glucose-6-phosphate dehydrogenase (G6PD), the principal source of NADPH, serves as an antioxidant enzyme to modulate the redox milieu and nitric oxide synthase activity. Deficient G6PD activity is associated with increased endothelial cell oxidant stress and diminished bioavailable nitric oxide (NO ⅐ ). Therefore, we examined whether overexpression of G6PD would decrease reactive oxygen species accumulation and increase bioavailable NO ⅐ in endothelial cells. Methods and Results-Adenoviral-mediated gene transfer of G6PD increased G6PD expression, activity, and NADPH levels in bovine aortic endothelial cells (BAECs). BAECs overexpressing G6PD demonstrated a significant reduction in reactive oxygen species accumulation when exposed to hydrogen peroxide, xanthine-xanthine oxidase, or tumor necrosis factor-␣ compared with BAECs with basal levels of G6PD. BAECs overexpressing G6PD maintained intracellular glutathione stores when exposed to oxidants because of increased activity of glutathione reductase, an effect that was not observed in endothelial cells with normal G6PD activity. Overexpression of G6PD was also associated with enhanced nitric oxide synthase activity, resulting in elevated levels of cGMP, nitrate, and nitrite, and this response was increased after stimulation with bradykinin. Conclusions-Overexpression

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Enhanced oxidative stress and accelerated cellular senescence in glucose-6-phosphate dehydrogenase (G6PD)-deficient human fibroblasts

Cited by 95 publications

References 36 publications

Downregulation of Connexin 43 Expression by High Glucose Induces Senescence in Glomerular Mesangial Cells

Downregulation of Connexin 43 Expression by High Glucose Induces Senescence in Glomerular Mesangial Cells

Endothelial cells maintain a reduced redox environment even as mitochondrial function declines

Glucose-6-Phosphate Dehydrogenase Overexpression Decreases Endothelial Cell Oxidant Stress and Increases Bioavailable Nitric Oxide

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