Evaluation of N ε-(3-formyl-3,4-dehydropiperidino)lysine as a novel biomarker for the severity of diabetic retinopathy

Zhang, Xiaohong; Lai, Yu-Wei; McCance, David R.; Uchida, Koji; McDonald, Denise; Gardiner, Tom; Stitt, Alan W.; Curtis, Tim M.

doi:10.1007/s00125-008-1071-3

Cited by 31 publications

(25 citation statements)

References 46 publications

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“…One study by Losado et al reported that concentrations of the ALE precursor, MDA, are elevated in type 1 patients with retinopathy when compared to diabetics without retinopathy and healthy controls [45]. More recently, we have demonstrated that haemoglobin levels of the ACR-derived ALE, FDPlysine, are associated with the severity of diabetic retinopathy in type 1 and type 2 diabetic patients [88]. Importantly, the relationship of FDP-lysine with retinopathy was unaltered after adjustment for HbA1c, or other clinical parameters.…”

Section: Clinical Correlates With Diabetic Retinopathysupporting

confidence: 48%

“…Lipid peroxidation is enhanced in diabetes, and diabetic patients have higher serum levels of MDA than non-diabetic subjects [30]. It has also been reported by our own group and others that FDP-lysine-and HNE-modified proteins accumulate in serum of patients with diabetes compared to control individuals [74,88]. At present, however, our understanding of the role of ALEs in the pathogenesis of diabetic complications, particularly retinopathy, lags far behind that which is currently known about AGEs.…”

Section: Biochemistry Of Age and Ale Formationmentioning

confidence: 78%

“…During diabetes there is significant upregulation of this receptor where it co-localises with GFAP and vimentin [87,88]. It is worth noting that some of the other non-AGE RAGE ligands also occur in the retina, and these may be capable of inducing pro-inflammatory signalling.…”

Section: Age/ale Inhibition and Prevention Of Retinopathymentioning

confidence: 99%

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Diabetes-related adduct formation and retinopathy

Stitt

Curtis

2011

j ocul biol dis inform

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The pathogenesis of diabetic retinopathy is complex, reflecting the array of systemic and tissue-specific metabolic abnormalities. A range of pathogenic pathways are directly linked to hyperglycaemia and dyslipidaemia, and the retina appears to be exquisitely sensitive to damage. Establishing the biochemical and molecular basis for this pathology remains an important research focus. This review concentrates on the formation of a range of protein adducts that form after exposure to modifying intermediates known to be elevated during diabetes. These so-called advanced glycation end products (AGEs) and advanced lipoxidation end products (ALEs) are thought to play an important role in the initiation and progression of diabetic retinopathy, and mechanisms leading to dysfunction and death of various retinal cells are becoming understood. Perspective is provided on AGE/ALE formation in the retina and the impact that such adducts have on retinal cell function. There will be emphasis placed on the role of the receptor for AGEs and how this may modulate retinal pathology, especially in relation to oxidative stress and inflammation. The review will conclude by discussion of strategies to inhibit AGE/ALE formation or harmful receptor interactions in order to prevent disease progression from the point of diabetes diagnosis to sight-threatening proliferative diabetic retinopathy and diabetic macular oedema.

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Section: Clinical Correlates With Diabetic Retinopathysupporting

confidence: 48%

Section: Biochemistry Of Age and Ale Formationmentioning

confidence: 78%

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Diabetes-related adduct formation and retinopathy

Stitt

Curtis

2011

j ocul biol dis inform

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“…Dark grey bars, pyridoxamine-treated diabetic; light grey bars, diabetic; black bars, non-diabetic. ***p<0.001 vs NonDb; † † p< 0.01 vs Db levels of the acrolein-derived FDP-lysine are associated with severity of retinopathy in type 1 and type 2 diabetic patients [34].…”

Section: Discussionmentioning

confidence: 98%

Müller glial dysfunction during diabetic retinopathy in rats is linked to accumulation of advanced glycation end-products and advanced lipoxidation end-products

et al. 2010

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Aims/hypothesis The impact of AGEs and advanced lipoxidation end-products (ALEs) on neuronal and Müller glial dysfunction in the diabetic retina is not well understood. We therefore sought to identify dysfunction of the retinal Müller glia during diabetes and to determine whether inhibition of AGEs/ALEs can prevent it. Methods Sprague-Dawley rats were divided into three groups: (1) non-diabetic; (2) untreated streptozotocininduced diabetic; and (3) diabetic treated with the AGE/ ALE inhibitor pyridoxamine for the duration of diabetes. Rats were killed and their retinas were evaluated for neuroglial pathology. Results AGEs and ALEs accumulated at higher levels in diabetic retinas than in controls (p<0.001). AGE/ALE immunoreactivity was significantly diminished by pyridoxamine treatment of diabetic rats. Diabetes was also associated with the up-regulation of the oxidative stress marker haemoxygenase-1 and the induction of glial fibrillary acidic protein production in Müller glia (p<0.001). Pyridoxamine treatment of diabetic rats had a significant beneficial effect on both variables (p < 0.001). Diabetes also significantly altered the normal localisation of the potassium inwardly rectifying channel Kir4.1 and the water channel aquaporin 4 to the Müller glia end-feet interacting with retinal capillaries. These abnormalities were prevented by pyridoxamine treatment. Conclusions/interpretation While it is established that AGE/ALE formation in the retina during diabetes is linked to microvascular dysfunction, this study suggests that these pathogenic adducts also play a role in Müller glial dysfunction.

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“…Increased levels of hemoglobin FDP-Lys have been associated with the severity of diabetic retinopathy in type 1 and type 2 diabetic patients, and its formation is involved in the pathogenesis of this sight-threatening complication of diabetes [71].…”

Section: Ex Vivo-in Vivo Studiesmentioning

confidence: 99%

Protein modification by acrolein: Relevance to pathological conditions and inhibition by aldehyde sequestering agents

Aldini

Orioli

Carini

2011

Molecular Nutrition Food Res

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Acrolein (ACR) is a toxic and highly reactive α,β-unsaturated aldehyde widely distributed in the environment as a common pollutant and generated endogenously mainly by lipoxidation reactions. Its biological effects are due to its ability to react with the nucleophilic sites of proteins, to form covalently modified biomolecules which are thought to be involved as pathogenic factors in the onset and progression of many pathological conditions such as cardiovascular and neurodegenerative diseases. Functional impairment of structural proteins and enzymes by covalent modification (crosslinking) and triggering of key cell signalling systems are now well-recognized signs of cell and tissue damage induced by reactive carbonyl species (RCS). In this review, we mainly focus on the in vitro and in vivo evidence demonstrating the ability of ACR to covalently modify protein structures, in order to gain a deeper insight into the dysregulation of cellular and metabolic pathways caused by such modifications. In addition, by considering RCS and RCS-modified proteins as drug targets, this survey will provide an overview on the newly developed molecules specifically tested for direct or indirect ACR scavenging, and the more significant studies performed in the last years attesting the efficacy of compounds already recognized as promising aldehyde-sequestering agents.

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Evaluation of N ε-(3-formyl-3,4-dehydropiperidino)lysine as a novel biomarker for the severity of diabetic retinopathy

Cited by 31 publications

References 46 publications

Diabetes-related adduct formation and retinopathy

Diabetes-related adduct formation and retinopathy

Müller glial dysfunction during diabetic retinopathy in rats is linked to accumulation of advanced glycation end-products and advanced lipoxidation end-products

Protein modification by acrolein: Relevance to pathological conditions and inhibition by aldehyde sequestering agents

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