Methylglyoxal administration induces diabetes-like microvascular changes and perturbs the healing process of cutaneous wounds

Berlanga, Jorge; Cibrián, Danay; Guillén, Isabel; Freyre, Freya; Alba, José Suárez; López-Saura, Pedro; Merino, Nelsón; Aldama, Alfredo; Quintela, Ana María; Triana, María Eugenia; Montequin, J Fernandez; Ajamieh, Hussam; Urquiza, Dioslaida; Ahmed, Naila; Thornalley, Paul J.

doi:10.1042/cs20050026

Cited by 142 publications

(123 citation statements)

References 45 publications

(42 reference statements)

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“…Previous studies have shown that diets high in MG-derived AGEs (and therefore, presumably, MG) are able to induce vascular inflammation and atherogenesis in diabetic apoE KO mice (37), but control mice were unaffected. Other studies have suggested that MG may be a pathogenic factor for the development of endothelial dysfunction (38), renal damage (39), insulin resistance (40), and macrophage activation (41), all of which may have contributed to atherogenesis in our model. It has also been reported that exposure to MG may be associated with the development of dyslipidemia (40) and/or hypertension (38).…”

Section: Discussionmentioning

confidence: 90%

“…Other studies have suggested that MG may be a pathogenic factor for the development of endothelial dysfunction (38), renal damage (39), insulin resistance (40), and macrophage activation (41), all of which may have contributed to atherogenesis in our model. It has also been reported that exposure to MG may be associated with the development of dyslipidemia (40) and/or hypertension (38). In our studies, neither MG administration nor BBGC modified lipid or blood pressure levels, although our mice had marked dyslipidemia due to genetic deletion of the apoE gene, a model in which diabetes itself has only modest effects on already elevated lipid levels (Table 1).…”

Section: Discussionmentioning

confidence: 90%

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Dicarbonyl Stress in the Absence of Hyperglycemia Increases Endothelial Inflammation and Atherogenesis Similar to That Observed in Diabetes

et al. 2014

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The deleterious effects of high glucose levels and enhanced metabolic flux on the vasculature are thought to be mediated by the generation of toxic metabolites, including reactive dicarbonyls like methylglyoxal (MG). In this article, we demonstrate that increasing plasma MG to levels observed in diabetic mice either using an exogenous source (1% in drinking water) or generated following inhibition, its primary clearance enzyme, glyoxalase-1 (with 50 mg/kg IP bromobenzyl-glutathione cyclopentyl diester every second day), was able to increase vascular adhesion and augment atherogenesis in euglycemic apolipoprotein E knockout mice to a similar magnitude as that observed in hyperglycemic mice with diabetes. The effects of MG appear partly mediated by activation of the receptor for advanced glycation end products (RAGE), as deletion of RAGE was able to reduce inflammation and atherogenesis associated with MG exposure. However, RAGE deletion did not completely prevent inflammation or vascular damage, possibly because the induction of mitochondrial oxidative stress by dicarbonyls also contributes to inflammation and atherogenesis. Such data would suggest that a synergistic combination of RAGE antagonism and antioxidants may offer the greatest utility for the prevention and management of diabetic vascular complications.

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 90%

Dicarbonyl Stress in the Absence of Hyperglycemia Increases Endothelial Inflammation and Atherogenesis Similar to That Observed in Diabetes

et al. 2014

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“…Prospective Diabetes Study [3] strongly suggest the importance of hyperglycemia in the pathogenesis of chronic complications of diabetes mellitus including diabetic renal disease. Hyperglycemia leads to diabetic nephropathy (DN) via multiple mechanisms, and among them increased aldose reductase (AR) activity [4,5], nonenzymatic glycation and glycooxidation [6,7], activation of protein kinase C (PKC) and hexosamine pathway [8][9][10], arachidonic acid metabolism via 12/15-lipoxygenase pathway [11,12], and triose phosphate accumulation [13] are the best studied. Growing evidence obtained in diabetic animals (primarily, STZ (streptozotocin)-diabetic rats and mice) [14][15][16][17] as well as cell culture models [18][19][20] implicates free radicals and the potent oxidant peroxynitrite (a product of superoxide anion radical reaction with nitric oxide) in both hemodynamic and metabolic abnormalities leading to DN.…”

Section: Introductionmentioning

confidence: 99%

Aldose reductase inhibition counteracts nitrosative stress and poly(ADP-ribose) polymerase activation in diabetic rat kidney and high-glucose-exposed human mesangial cells

Drel

Pacher²,

Stevens

et al. 2006

Free Radical Biology and Medicine

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Both increased aldose reductase (AR) activity and oxidative/nitrosative stress have been implicated in the pathogenesis of diabetic nephropathy, but the relation between the two factors remains a subject of debate. This study evaluated the effects of AR inhibition on nitrosative stress and poly(ADPribose) polymerase (PARP) activation in diabetic rat kidney and high-glucose-exposed human mesangial cells. In animal experiments, control (C) and streptozotocin-diabetic (D) rats were treated with/without the AR inhibitor fidarestat (F, 16 mg kg −1 day −1 ) for 6 weeks starting from induction of diabetes. Glucose, sorbitol, and fructose concentrations were significantly increased in the renal cortex of D vs C (p < 0.01 for all three comparisons), and sorbitol pathway intermediate, but not glucose, accumulation, was completely prevented in D + F. F at least partially prevented diabetesinduced increase in kidney weight as well as nitrotyrosine (NT, a marker of peroxynitrite-induced injury and nitrosative stress), and poly(ADP-ribose) (a marker of PARP activation) accumulation, assessed by both immunohistochemistry and Western blot analysis, in glomerular and tubular compartments of the renal cortex. In vitro studies revealed the presence of both AR and PARP-1 in human mesangial cells, and none of these two variables were affected by high glucose or F treatment. Nitrosylated and poly(ADP-ribosyl)ated proteins (Western blot analysis) accumulated in cells cultured in 30 mM D-glucose (vs 5.55 mM glucose, p < 0.01), but not in cells cultured in 30 mM Lglucose or 30 mM D-glucose plus 10 μM F. AR inhibition counteracts nitrosative stress and PARP activation in the diabetic renal cortex and high-glucose-exposed human mesangial cells. These findings reveal new beneficial properties of the AR inhibitor F and provide the rationale for detailed studies of F on diabetic nephropathy.

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“…Methylglyoxal reacts with cysteine, lysine and arginine residues on proteins to form advanced glycation end-products (AGEs) that affect protein function (5,6). Administration of MG to mice, rats, or cells in culture, results in physiological changes observed in diabetic patients such as collagen accumulation in kidneys, hypercholesterolemia, microvasculature degeneration, and insulin resistance (7)(8)(9).…”

mentioning

confidence: 99%

Evidence Against a Role for the Parkinsonism-associated Protein DJ-1 in Methylglyoxal Detoxification

Pfaff

Fleming

Nawroth

et al. 2017

Journal of Biological Chemistry

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Edited by Gerald W. HartMethylglyoxal (MG) is a reactive metabolite that forms adducts on cysteine, lysine and arginine residues of proteins, thereby affecting their function. Methylglyoxal is detoxified by the Glyoxalase system, consisting of two enzymes, Glo1 and Glo2, that act sequentially to convert MG into D-lactate. Recently, the Parkinsonism-associated protein DJ-1 was described in vitro to have glyoxalase activity, thereby detoxifying the MG metabolite, or deglycase activity, thereby removing the adduct formed by MG on proteins. Since Drosophila is an established model system to study signaling, neurodegeneration, and metabolic regulation in vivo, we asked whether DJ-1 contributes to MG detoxification in vivo. Using both DJ-1 knockdown in Drosophila cells in culture, and DJ-1␤ knock-out flies, we could detect no contribution of DJ-1 to survival to MG challenge or to accumulation of MG protein adducts. Furthermore, we provide data suggesting that the previously reported deglycation activity of DJ-1 can be ascribed to a TRIS buffer artifact.

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Methylglyoxal administration induces diabetes-like microvascular changes and perturbs the healing process of cutaneous wounds

Cited by 142 publications

References 45 publications

Dicarbonyl Stress in the Absence of Hyperglycemia Increases Endothelial Inflammation and Atherogenesis Similar to That Observed in Diabetes

Dicarbonyl Stress in the Absence of Hyperglycemia Increases Endothelial Inflammation and Atherogenesis Similar to That Observed in Diabetes

Aldose reductase inhibition counteracts nitrosative stress and poly(ADP-ribose) polymerase activation in diabetic rat kidney and high-glucose-exposed human mesangial cells

Evidence Against a Role for the Parkinsonism-associated Protein DJ-1 in Methylglyoxal Detoxification

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