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      Temporal Increases in Urinary Carboxymethyllysine Correlate with Albuminuria Development in Diabetes

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          Abstract

          Background/Aims: Advanced glycation end products (AGEs) mediate progressive tissue damage in diabetic nephropathy; however, their utility as a noninvasive reliable biomarker of progressive diabetic nephropathy remains to be determined. In this study, we investigated the temporal accumulation of the AGE carboxymethyllysine (CML) at various sites in a model of experimental diabetic nephropathy. Methods: Diabetic rats were followed for 1, 4, 8, 16 and 32 weeks. Glomerular filtration rate and urinary albumin excretion were measured. CML was determined in the plasma, urine, renal cortical mitochondria and cytosol by an in-house ELISA. Gene expression of AGE receptors were quantified by real-time PCR and urinary excretion of 8-hydroxy-2′-deoxyguanosine (8-OHdG) was determined by EIA. Results: Four weeks after diabetes induction, urinary CML excretion was increased, which preceded the excretion of urinary albumin and continued to rise progressively until 32 weeks. Circulating, mitochondrial and cytosolic CML content and urinary excretion of 8-OHdG were increased 4 weeks after diabetes induction, but did not increase further with diabetes duration. Renal gene expression of AGE receptors was transiently upregulated at 1 week of diabetes, but this was not a sustained phenomenon. Conclusions: The most informative marker of progressive renal damage linked to the AGE pathway in experimental diabetic nephropathy is urinary excretion of CML, which now warrants clinical investigation as a potential noninvasive sensitive marker of progressive diabetic nephropathy.

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          Most cited references 32

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          Advanced glycosylation end products in tissue and the biochemical basis of diabetic complications.

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            Clinical review: The role of advanced glycation end products in progression and complications of diabetes.

            Diabetic complications appear to be multifactorial in origin, but in particular, the biochemical process of advanced glycation, which is accelerated in diabetes as a result of chronic hyperglycemia and increased oxidative stress, has been postulated to play a central role in these disorders. Advanced glycation involves the generation of a heterogenous group of chemical moieties known as advanced glycated end products (AGEs), this reaction occurring as a result of a nonenzymatic reaction with glucose interacting with proteins, lipids, and nucleic acids, and involves key intermediates such as methylglyoxal. In this review we report on how these AGEs may exert deleterious effects in diabetes, as well as address current strategies to interrupt the formation or action of AGEs. First, AGEs act directly to induce cross-linking of long-lived proteins such as collagen to promote vascular stiffness, and, thus, alter vascular structure and function. Second, AGEs can interact with certain receptors, such as the receptor for AGE, to induce intracellular signaling that leads to enhanced oxidative stress and elaboration of key proinflammatory and prosclerotic cytokines. Over the last decade, a large number of preclinical studies have been performed, targeting the formation and degradation of AGEs, as well as the interaction of these AGEs with receptors such as the receptor for AGE. It is hoped that over the next few years, some of these promising therapies will be fully evaluated in the clinical context with the ultimate aim to reduce the major economical and medical burden of diabetes, its vascular complications.
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              RAGE-induced cytosolic ROS promote mitochondrial superoxide generation in diabetes.

              Damaged mitochondria generate an excess of superoxide, which may mediate tissue injury in diabetes. We hypothesized that in diabetic nephropathy, advanced glycation end-products (AGEs) lead to increases in cytosolic reactive oxygen species (ROS), which facilitate the production of mitochondrial superoxide. In normoglycemic conditions, exposure of primary renal cells to AGEs, transient overexpression of the receptor for AGEs (RAGE) with an adenoviral vector, and infusion of AGEs to healthy rodents each induced renal cytosolic oxidative stress, which led to mitochondrial permeability transition and deficiency of mitochondrial complex I. Because of a lack of glucose-derived NADH, which is the substrate for complex I, these changes did not lead to excess production of mitochondrial superoxide; however, when we performed these experiments in hyperglycemic conditions in vitro or in diabetic rats, we observed significant generation of mitochondrial superoxide at the level of complex I, fueled by a sustained supply of NADH. Pharmacologic inhibition of AGE-RAGE-induced mitochondrial permeability transition in vitro abrogated production of mitochondrial superoxide; we observed a similar effect in vivo after inhibiting cytosolic ROS production with apocynin or lowering AGEs with alagebrium. Furthermore, RAGE deficiency prevented diabetes-induced increases in renal mitochondrial superoxide and renal cortical apoptosis in mice. Taken together, these studies suggest that AGE-RAGE-induced cytosolic ROS production facilitates mitochondrial superoxide production in hyperglycemic environments, providing further evidence of a role for the advanced glycation pathway in the development and progression of diabetic nephropathy.
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                Author and article information

                Journal
                AJN
                Am J Nephrol
                10.1159/issn.0250-8095
                American Journal of Nephrology
                S. Karger AG
                0250-8095
                1421-9670
                2011
                July 2011
                06 June 2011
                : 34
                : 1
                : 9-17
                Affiliations
                Glycation and Diabetes Complications Laboratory, Baker IDI Heart and Diabetes Institute, and Departments of Immunology and Medicine, Monash University, Melbourne, Vic., Australia
                Author notes
                *Dr. Melinda Coughlan, Glycation and Diabetes Complications Laboratory, Baker IDI Heart and Diabetes Institute, PO Box 6492, St. Kilda Rd Central, Melbourne, VIC 8008 (Australia), Tel. +61 38 532 1278, E-Mail Melinda.Coughlan@bakeridi.edu.au
                Article
                328581 Am J Nephrol 2011;34:9–17
                10.1159/000328581
                21654162
                © 2011 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 4, Tables: 1, Pages: 9
                Categories
                Original Report: Laboratory Investigation

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