Relationship between Markers of Endothelial Dysfunction, Oxidant Injury and Tubular Damage in Patients with Insulin-Dependent Diabetes Mellitus

Yaqoob, Muhammad; Patrick, A. W.; McClelland, Peter D.; Stevenson, A.; Mason, H. J.; White, Michael C.; Bell, G. H.

doi:10.1042/cs0850557

Cited by 50 publications

(29 citation statements)

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“…Plasma thrombomodulin has been described as marker of endothelial activation and endothelial damage which correlates with diabetic microvascular disease [34,45] and albuminuria [46,47]. Raised plasma thrombomodulin concentrations have been reported in patients with increased oxidant injury, tubular damage and proteinuria [48]. Accordingly, thrombomodulin plasma concentrations correlated positively with albuminuria (Pearson's coefficient r = 0.341, data not shown) and NF-kB binding activity determined in PBMC of 20 of our study subjects (Pearson's coefficient r = 0.337; Fig.…”

Section: Resultsmentioning

confidence: 99%

Peripheral blood mononuclear cells isolated from patients with diabetic nephropathy show increased activation of the oxidative-stress sensitive transcription factor NF-kB

et al. 1999

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Increased oxidative stress generated by hyperglycaemia, hyperlipidaemia or the presence of advanced glycation endproducts (AGEs) or both is regarded as an important mediator of late diabetic complications [1]. A clear relation between the quality of glycaemic control and the presence of free radicals has been shown thereby relating the appearance of oxidative stress to the underlying metabolic disorder rather than to the complication itself [2]. The presence of oxygen free radicals and the simultaneous decline of antioxidative defence mechanisms observed in diabetic patients could therefore promote the development of late diabetic complications [1, 3±5].Oxidative stress has been proposed as a major cause of diabetic nephropathy [6±9]. Animal models implicate that oxidative stress accompanying the early onset of diabetes increases the kidney's susceptibility to develop diabetic nephropathy [10]. One possible mechanism for this is the activation of the oxidative stress sensitive transcription factor NF-kB [6, 11±13]. Translocation of activated NF-kB into the nucleus results in gene expression of NF-kB controlled Diabetologia (1999) 42: 222±232 Peripheral blood mononuclear cells isolated from patients with diabetic nephropathy show increased activation of the oxidative-stress sensitive transcription factor NF-kB

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Section: Resultsmentioning

confidence: 99%

Peripheral blood mononuclear cells isolated from patients with diabetic nephropathy show increased activation of the oxidative-stress sensitive transcription factor NF-kB

et al. 1999

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“…In this context, previous clinical studies have correlated plasma markers of oxidant stress and EC perturbation in diabetes with both vascular dysfunction and subsequent vascular complications (21). Alternatively (or in addition), the pathogenetic effect of AGEs could also be indirect, such as by induction of cytokines (e.g., tumor necrosis factor-␣) (22) or growth factors (vascular permeability factor/vascular endothelial growth factor).…”

Section: Discussionmentioning

confidence: 99%

Receptor-mediated endothelial cell dysfunction in diabetic vasculopathy. Soluble receptor for advanced glycation end products blocks hyperpermeability in diabetic rats.

Wautier¹,

Zoukourian²,

Chappey³

et al. 1996

J. Clin. Invest.

522

325

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Dysfunctional endothelium is associated with and, likely, predates clinical complications of diabetes mellitus, by promoting increased vascular permeability and thrombogenicity. Irreversible advanced glycation end products (AGEs), resulting from nonenzymatic glycation and oxidation of proteins or lipids, are found in plasma, vessel wall, and tissues and have been linked to the development of diabetic complications. The principal means through which AGEs exert their cellular effects is via specific cellular receptors, one of which, receptor for AGE (RAGE), is expressed by endothelium. We report that blockade of RAGE inhibits AGE-induced impairment of endothelial barrier function, and reverses, in large part, the early vascular hyperpermeability observed in diabetic rats. Inhibition of AGE-and dia- IntroductionExposure of proteins or lipids to reducing sugars results in nonenzymatic glycation and oxidation. Initially, reversible early glycation adducts, Schiff bases and Amadori products, form on free amino groups (1). Further complex molecular rearrangements produce irreversible advanced glycation end products (AGEs):1 heterogeneous structures of yellow-brown color, characteristic fluorescence, and a propensity to form cross-links, which generate reactive oxygen intermediates and interact with specific cellular receptors (1-4). The presence of AGEs in tissue has been linked to development of vasculopathy, especially in the setting of diabetes (1, 3). AGE-modified adducts on long-lived proteins in extracellular matrix alter basement membrane structure by trapping plasma macromolecules and by increasing vessel wall rigidity through formation of cross-links (3). The principal means through which AGEs influence cellular properties is by binding to specific receptors (4-6), the best characterized of which is the receptor for AGEs (RAGE), a member of the immunoglobulin superfamily expressed by endothelial cells (ECs), smooth muscle cells, and mononuclear phagocytes (7), cells central to both vascular homeostasis and the pathogenesis of vascular lesions. A potential role for RAGE in vascular dysfunction is suggested by two lines of evidence: ( a ) engagement of AGEs by cellular RAGE affects critical properties of these cells in a manner contributory to vascular dysfunction (4); and ( b ) there is enhanced expression of RAGE in diabetic vasculopathy and in arteriosclerotic and other vascular lesions, such as inflammatory vasculitides (8).Increased vascular permeability is characteristic of diabetic vasculopathy (9), even at the earliest stages in which microalbuminuria may be the only harbinger of vascular complications yet to come (10). As ECs are the critical guardians of vascular barrier function, we postulated that AGEs in plasma or the subendothelium would promote vascular hyperpermeability by interacting with RAGE. We demonstrate that when diabetic rat red cells bearing AGEs are infused into normal animals, increased vascular permeability results, an effect which is prevented by blockade of RAGE. Hyperperme...

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“…Both clinical and experimental studies suggest that free radicals as well as endothelial dysfunction may play a key role in the pathogenesis of diabetic nephropathy [15,17]. …”

Section: Discussionmentioning

confidence: 99%

Effect of aminoguanidine on lipid peroxidation and activities of antioxidant enzymes in the diabetic kidney

Kędziora–Kornatowska

Luciak

1998

IUBMB Life

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SUMMARYThe aim of this study was to examine lipid peroxidation and activities of key antioxidant enzymes in kidneys of rats with streptozotocin (STZ)-induced diabetes and the effect of aminoguanidine on diabetes-induced alterations. Three groups, 6 rats each, were studied: control animals, not treated diabetic rats and rats treated with aminoguanidine (AG; 1 g/liter of drinking water) After 6 and 12 weeks the animals were sacrificed and lipid peroxidation products and activities of antioxidant enzymes were determined in their kidney homogenates. Malondialdehyde (MDA) content was significantly elevated and activities of SOD and catalase decreased in the kidneys of STZ-diabetic rats. AG treatment attenuated the increase in MDA content and diminutions of activities of SOD and catalase in the kidneys of diabetic rats. These results confirm oxidative stress in the kidney of rats with STZ diabetes and point to an antioxidant effect of AG in experimental diabetes.

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Relationship between Markers of Endothelial Dysfunction, Oxidant Injury and Tubular Damage in Patients with Insulin-Dependent Diabetes Mellitus

Cited by 50 publications

References 0 publications

Peripheral blood mononuclear cells isolated from patients with diabetic nephropathy show increased activation of the oxidative-stress sensitive transcription factor NF-kB

Peripheral blood mononuclear cells isolated from patients with diabetic nephropathy show increased activation of the oxidative-stress sensitive transcription factor NF-kB

Receptor-mediated endothelial cell dysfunction in diabetic vasculopathy. Soluble receptor for advanced glycation end products blocks hyperpermeability in diabetic rats.

Effect of aminoguanidine on lipid peroxidation and activities of antioxidant enzymes in the diabetic kidney

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