The pathogenesis of diabetic complications: the role of DNA injury and poly(ADP-ribose) polymerase activation in peroxynitrite-mediated cytotoxicity

Kiss, Levente; Szabó, Csaba

doi:10.1590/s0074-02762005000900007

Cited by 38 publications

(27 citation statements)

References 97 publications

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“…This finding is consistent with previous studies of diabetic rats (9,16,19). Hyperglycemia was also associated with reactive microgliosis, but without evidence of neuronal injury.…”

Section: Discussionsupporting

confidence: 93%

“…Superoxides and nitrogen-based free radicals form peroxynitrate that can cause DNA strand breakage and activate poly(ADP-ribose) polymerase-1 (PARP-1) (8). PARP-1 is a nuclear enzyme involved in cell survival by binding to DNA breakage sites and poly(ADP-ribosyl)ation (PAR) of DNA repair proteins such as DNA ligases, polymerases, and histones in a NAD + dependent manner (9). However, excess PARP-1 activation can lead to cell death via NAD + depletion and PARmediated release of apoptosis inducing factor from the mitochondria (10).…”

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confidence: 99%

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Recurrent hypoinsulinemic hyperglycemia in neonatal rats increases PARP-1 and NF-κB expression and leads to microglial activation in the cerebral cortex

et al. 2015

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Background: Hyperglycemia is a common metabolic problem in extremely low-birth-weight preterm infants. Neonatal hyperglycemia is associated with increased mortality and brain injury. Glucose-mediated oxidative injury may be responsible. Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear enzyme involved in DNA repair and cell survival. However, PARP-1 overactivation leads to cell death. NF-κB is coactivated with PARP-1 and regulates microglial activation. The effects of recurrent hyperglycemia on PARP-1/NF-κB expression and microglial activation are not well understood. Methods: Rat pups were subjected to recurrent hypoinsulinemic hyperglycemia of 2 h duration twice daily from postnatal (P) day 3-P12 and killed on P13. mRNA and protein expression of PARP-1/NF-κB and their downstream effectors were determined in the cerebral cortex. Microgliosis was determined using CD11 immunohistochemistry. results: Recurrent hyperglycemia increased PARP-1 expression confined to the nucleus and without causing PARP-1 overactivation and cell death. NF-κB mRNA expression was increased, while IκB mRNA expression was decreased. inducible nitric oxide synthase (iNOS), endothelial nitric oxide synthase (eNOS), and neuronal nitric oxide synthase (nNOS) mRNA expressions were decreased. Hyperglycemia significantly increased the number of microglia. conclusion: Recurrent hyperglycemia in neonatal rats is associated with upregulation of PARP-1 and NF-κB expression and subsequent microgliosis but not neuronal cell death in the cerebral cortex.

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“…This finding is consistent with previous studies of diabetic rats (9,16,19). Hyperglycemia was also associated with reactive microgliosis, but without evidence of neuronal injury.…”

Section: Discussionsupporting

confidence: 93%

mentioning

confidence: 99%

Recurrent hypoinsulinemic hyperglycemia in neonatal rats increases PARP-1 and NF-κB expression and leads to microglial activation in the cerebral cortex

et al. 2015

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“…Ribosylation and nitration have been shown to inhibit GAPDH activity (15,33). We determined the levels of its ribosylation and nitration of retinal GAPDH.…”

Section: Resultsmentioning

confidence: 99%

Role of Glyceraldehyde 3-Phosphate Dehydrogenase in the Development and Progression of Diabetic Retinopathy

Kanwar

Kowluru

2009

Diabetes

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OBJECTIVE-Mitochondrial superoxide levels are elevated in the retina in diabetes, and manganese superoxide dismutase overexpression prevents the development of retinopathy. Superoxide inhibits glyceraldehyde-3-phosphate dehydrogenase (GAPDH), which activates major pathways implicated in diabetic complications, including advanced glycation end products (AGEs), protein kinase C, and hexosamine pathway. Our aim is to investigate the role of GAPDH in the development and progression of diabetic retinopathy and to elucidate the mechanism.RESEARCH DESIGN AND METHODS-Rats with streptozotocin-induced diabetes were in a state of poor control (GHb Ͼ11%) for 12 months, good control (GHb Ͻ7) soon after induction of diabetes, or poor control for 6 months with 6 months' good control. Retinal GAPDH, its ribosylation and nitration, AGEs, and PKC activation were determined and correlated with microvascular histopathology.RESULTS-In rats with poor control, retinal GAPDH activity and expressions were subnormal with increased ribosylation and nitration (25-30%). GAPDH activity was subnormal in both cytosol and nuclear fractions, but its protein expression and nitration were significantly elevated in nuclear fraction. Reinstitution of good control failed to protect inactivation of GAPDH, its covalent modification, and translocation to the nucleus. PKC, AGEs, and hexosamine pathways remained activated, and microvascular histopathology was unchanged. However, GAPDH and its translocation in good control rats were similar to those in normal rats.CONCLUSIONS-GAPDH plays a significant role in the development of diabetic retinopathy and its progression after cessation of hyperglycemia. Thus, therapies targeted toward preventing its inhibition may inhibit development of diabetic retinopathy and arrest its progression. Diabetes 58:227-234, 2009 R etinopathy is a multifactorial sight-threatening complication of diabetes. It is a progressive disease associated with chronic hyperglycemia (1). Although many glucose-induced retinal metabolic abnormalities are postulated to contribute to its development, the exact mechanism remains elusive (2-5). We have shown that in diabetes, retinal mitochondria experience increased oxidative damage and the mitochondrial enzyme that scavenges superoxide (manganese superoxide dismutase [MnSOD]) prevents vascular histopathology that is characteristic of diabetic retinopathy (6 -8). Increased mitochondrial superoxide production inactivates glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in vascular endothelial cells, and inhibition of GAPDH is postulated to activate some of the key pathways that are associated with the development of diabetes complications, including increased formation of advanced glycation end products (AGEs) and activation of protein kinase C (PKC) and hexosamine pathway (9,10).GAPDH is a glycolytic enzyme that catalyzes the conversion of glyceraldehyde-3-phosphate to 1,3-bis-phosphoglycerate. Recent studies have shown that GAPDH is a protein with multiple cytoplasmic, membrane, and nuclear fun...

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“…Du et al (6) observed that PARP-specific inhibitors can reverse poly-ADP-ribosylation of GAPDH, and attenuate the inhibition of GAPDH. Other studies (7,8) showed that PARP specific inhibitors can inhibit poly-ADP activation induced by hyperglycemia, suggesting a pathogenic role for PARP in peritoneal fibrosis under high glucose conditions. Thus, the present study tested the hypothesis that high glucose may stimulate the poly-ADP pathway to mediate peritoneal fibrosis in both primary culture of rat PMC and a human PMC line.…”

Section: Introductionmentioning

confidence: 99%

Poly(ADP-ribose) polymerase-1 in high glucose-induced epithelial-mesenchymal transition during peritoneal fibrosis

Lei

Jiang

Zhu³

et al. 2011

Int J Mol Med

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Abstract. Peritoneal fibrosis is a major complication of continuous ambulatory peritoneal dialysis (CAPD). The present study tested the hypothesis that ADP-ribose polymerase-1 (PARP-1) may play a role in peritoneal epithelial-mesenchymal transition and fibrosis under high glucose conditions. High glucose (126 mmol/l)-induced peritoneal EMT and fibrosis via the PARP-1 mechanism was examined in the primary culture of rat peritoneal mesothelial cells (PMCs) and in the human peritoneal mesothelial cell line (HMrSv5) in the presence or absence of a PARP-1 inhibitor PJ34 (3x10 -6 M) or by knocking down PARP-1 with the PARP-1 siRNA technique. High glucose significantly increased PARP-1 expression and EMT as demonstrated by de novo expression of a mesenchymal marker α-SMA and loss of epithelial phenotype E-cadherin by both rat and human PMC, resulting in peritoneal fibrosis including up-regulation of plasminogen activator inhibitor-1 (PAI-1), collagen I, and fibronectin mRNA and protein expression. All these fibrotic responses induced by high glucose were significantly inhibited by the PARP-1 inhibitor PJ34 (all P<0.05) or by knocking down PARP-1 with the siRNA technique. Results from this study suggested that high glucose stimulates peritoneal EMT and fibrosis via a PARP-1-dependent mechanism, and targeting the PARP-1 may represent an alternative therapeutic potential for CAPD-related peritoneal fibrosis.

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The pathogenesis of diabetic complications: the role of DNA injury and poly(ADP-ribose) polymerase activation in peroxynitrite-mediated cytotoxicity

Abstract: Recent work has demonstrated that hyperglycemia-induced overproduction of superoxide by the mitochondrial electron-transport chain triggers several pathways of injury [(protein kinase C (PKC)

Cited by 38 publications

References 97 publications

Recurrent hypoinsulinemic hyperglycemia in neonatal rats increases PARP-1 and NF-κB expression and leads to microglial activation in the cerebral cortex

Recurrent hypoinsulinemic hyperglycemia in neonatal rats increases PARP-1 and NF-κB expression and leads to microglial activation in the cerebral cortex

Role of Glyceraldehyde 3-Phosphate Dehydrogenase in the Development and Progression of Diabetic Retinopathy

Poly(ADP-ribose) polymerase-1 in high glucose-induced epithelial-mesenchymal transition during peritoneal fibrosis

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