Neutrophil Aldose Reductase Activity and its Association with Established Diabetic Microvascular Complications

Dent, M. T.; Tebbs, S. E.; González, Ana-Maria; Ward, John D.; Wilson, Robin

doi:10.1111/j.1464-5491.1991.tb01628.x

Cited by 43 publications

(11 citation statements)

References 17 publications

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“…35 Accordingly, increased AR expression under hyperglycemic conditions has been shown in different cell types. 36,37 Here, we extend this finding to human monocyte-derived macrophages. According to our results, 4-HNE is a key constituent of oxLDL responsible for AR upregulation.…”

Section: Gleissner Et Al Aldose Reductase In Foam Cells 1141mentioning

confidence: 60%

Upregulation of Aldose Reductase During Foam Cell Formation as Possible Link Among Diabetes, Hyperlipidemia, and Atherosclerosis

Gleissner

Sanders

Nadler

et al. 2008

ATVB

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Objective-Aldose reductase (AR) is the rate-limiting enzyme of the polyol pathway. In diabetes, it is related to microvascular complications. We discovered AR expression in foam cells by gene chip screening and hypothesized that it may be relevant in atherosclerosis. Methods and Results-AR gene expression and activity were found to be increased in human blood monocyte-derived macrophages during foam cell formation induced by oxidized LDL (oxLDL, 100 g/mL). AR activity as photometrically determined by NADPH consumption was effectively inhibited by the AR inhibitor epalrestat. oxLDL-dependent AR upregulation was further increased under hyperglycemic conditions (30 mmol/L D-glucose) as compared to osmotic control, suggesting a synergistic effect of hyperlipidemia and hyperglycemia. AR was also upregulated by 4-hydroxynonenal, a constituent of oxLDL. Upregulation was blocked by an antibody to CD36. AR inhibition resulted in reduction of oxLDL-induced intracellular oxidative stress as determined by 2Ј7Ј-dichlorofluoresceine diacetate (H 2 DCFDA) fluorescence, indicating that proinflammatory effects of oxLDL are partly mediated by AR.

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Section: Gleissner Et Al Aldose Reductase In Foam Cells 1141mentioning

confidence: 60%

Upregulation of Aldose Reductase During Foam Cell Formation as Possible Link Among Diabetes, Hyperlipidemia, and Atherosclerosis

Gleissner

Sanders

Nadler

et al. 2008

ATVB

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“…S1). It has been shown that glucose challenge indeed induces ROS production in neutrophils [19] and that the polyol pathway in neutrophils is activated in patients with diabetic microvascular complications [20,21]. …”

Section: Resultsmentioning

confidence: 99%

Circulating Neutrophil Extracellular Trap Levels in Well-Controlled Type 2 Diabetes and Pathway Involved in Their Formation Induced by High-Dose Glucose

et al. 2016

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Objectives: Although intensive therapy for type 2 diabetes (T2D) prevents microvascular complications, 10% of well-controlled T2D patients develop microangiopathy. Therefore, the identification of risk markers for microvascular complications in well-controlled T2D patients is important. Recent studies have demonstrated that high-dose glucose induces neutrophil extracellular trap (NET) formation, which can be a risk for microvascular disorders. Thus, we attempted to determine the correlation of circulating NET levels with clinical/laboratory parameters in well-controlled T2D patients and to reveal the mechanism of NET formation induced by high-dose glucose. Methods: Circulating NET levels represented by myeloperoxidase (MPO)-DNA complexes in the serum of 11 well-controlled T2D patients and 13 healthy volunteers were determined by enzyme-linked immunosorbent assay. The pathway involved in the NET formation induced by high-dose glucose was determined using specific inhibitors. Results: Serum MPO-DNA complex levels weresignificantly higher in some well-controlled T2D patients in correlation with the clinical/laboratory parameters which have been regarded as risk markers for microvascular complications. The aldose reductase inhibitor, ranirestat, could inhibit the NET formation induced by high-dose glucose. Conclusions: Elevated levels of circulating NETs can be a risk marker for microvascular complications in well-controlled T2D patients. The polyol pathway is involved in the NET formation induced by high-dose glucose.

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“…Erythrocytes and neutrophils of patients with T1DM as well as T2DM and microvascular disease have elevated ALR2 enzyme activities as well as protein levels compared to those with no complications [48][49][50][51][52][53][54][55][56][57]. In T1DM, those patients with the highest ALR2 enzyme activity were more than four times more likely to develop diabetic microvascular disease than those whose activity was similar to normal subjects.…”

Section: Aldose Reductase Enzyme and Protein Expression In Diabetic Mmentioning

confidence: 99%

Polymorphisms of the Aldose Reductase Gene and Susceptibility to Diabetic Microvascular Complications

Ag¹

2003

CMC

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Diabetes is a major cause of mortality and morbidity due to the long term microvascular complications of this disease. There is now convincing evidence to show that genetic factors together with elevated blood glucose play an important role in the susceptibility to diabetic nephropathy as well as retinopathy. The polyol pathway is thought to play an important role in the pathogenesis of diabetic microvascular complications. Aldose reductase is the first and rate-limiting enzyme of the polyol pathway. Polymorphisms in the promoter region as well as elsewhere in the gene have been associated with susceptibility to nephropathy, retinopathy as well as diabetic neuropathy. These associations have been replicated in patients with either type 1 or type 2 diabetes mellitus as well as across ethnic groups. These polymorphisms in the promoter region are also associated with expression of the gene. Although clinical trials using inhibitors of aldose reductase to treat diabetic microvascular complications have largely been unsuccessful, the identification of the susceptibility genes may help in the design of future drug regimens.

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Neutrophil Aldose Reductase Activity and its Association with Established Diabetic Microvascular Complications

Cited by 43 publications

References 17 publications

Upregulation of Aldose Reductase During Foam Cell Formation as Possible Link Among Diabetes, Hyperlipidemia, and Atherosclerosis

Upregulation of Aldose Reductase During Foam Cell Formation as Possible Link Among Diabetes, Hyperlipidemia, and Atherosclerosis

Circulating Neutrophil Extracellular Trap Levels in Well-Controlled Type 2 Diabetes and Pathway Involved in Their Formation Induced by High-Dose Glucose

Polymorphisms of the Aldose Reductase Gene and Susceptibility to Diabetic Microvascular Complications

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