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Advanced glycation endproducts in the pathogenesis of chronic kidney disease
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Rabbani, Naila and Thornalley, Paul J. (2018) Advanced glycation endproducts in the pathogenesis of chronic kidney disease. Kidney International, 93 (4). pp. 803-813. doi:10.1016/j.kint.2017.11.034
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WRAP-advanced-glycation-endproducts-pathogenesis-chronic-kidney-Rabbani-2018.pdf - Accepted Version - Requires a PDF viewer. Available under License Creative Commons Attribution Non-commercial No Derivatives 4.0. Download (773Kb) | Preview |
Official URL: http://doi.org/10.1016/j.kint.2017.11.034
Abstract
Advanced glycation endproducts (AGEs) are stable post-translational modifications of proteins formed by the spontaneous reaction with glucose and related metabolites. Important AGEs quantitatively are methylglyoxal (MG)-derived hydroimidazolone MG-H1, Nε- carboxymethyl-lysine (CML) and glucosepane. They contribute to the development of chronic kidney disease (CKD). Cellular proteolysis of AGE-modified proteins forms AGE free adducts, glycated amino acids, which are cleared by the kidneys and excreted in urine. Dietary AGEs mainly supplement the endogenous flux of AGE free adduct formation. AGE free adducts accumulate markedly in plasma with decline in glomerular filtration rate. A key precursor of AGEs is the dicarbonyl metabolite, MG, which is metabolised by glyoxalase 1 (Glo1) of the cytoplasmic glyoxalase system. Proteins susceptible to MG modification are called collectively the “dicarbonyl proteome”. Abnormal increase of MG “dicarbonyl stress” and is a characteristic of CKD, driven by down regulation of renal Glo1, increasing flux of MG-H1 formation. Protein inactivation and dysfunction linked to the dicarbonyl proteome contributes to CKD development. The receptor for AGEs, RAGE, is important in development of CKD but its interaction with AGEs in vivo remains enigmatic; other ligands and ternary complexation may be influential. Prevention of diabetic kidney disease (DKD) by overexpression of Glo1 in transgenic animal models has stimulated the development of small molecule inducers of Glo1 expression, “Glo1 inducers”, to prevent AGE formation. trans- Resveratrol-hesperetin combination therapy is a Glo1 inducer. In clinical trial it gave a profound improvement in insulin resistance and vascular inflammation. It may find future therapeutic application for treatment of DKD.
| Item Type: | Journal Article | ||||||||
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| Subjects: | R Medicine > RC Internal medicine | ||||||||
| Divisions: | Faculty of Medicine > Warwick Medical School > Biomedical Sciences Faculty of Medicine > Warwick Medical School > Biomedical Sciences > Translational & Experimental Medicine Faculty of Medicine > Warwick Medical School |
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| Library of Congress Subject Headings (LCSH): | Chronic renal failure -- Pathogenesis, Metabolites, Glyoxalase | ||||||||
| Journal or Publication Title: | Kidney International | ||||||||
| Publisher: | Elsevier Inc. | ||||||||
| ISSN: | 0085-2538 | ||||||||
| Official Date: | April 2018 | ||||||||
| Dates: |
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| Volume: | 93 | ||||||||
| Number: | 4 | ||||||||
| Page Range: | pp. 803-813 | ||||||||
| DOI: | 10.1016/j.kint.2017.11.034 | ||||||||
| Status: | Peer Reviewed | ||||||||
| Publication Status: | Published | ||||||||
| Access rights to Published version: | Restricted or Subscription Access | ||||||||
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