Uremic Toxicity of Advanced Glycation End Products in CKD
Total Page：16
File Type：pdf, Size：1020Kb
BRIEF REVIEW www.jasn.org Uremic Toxicity of Advanced Glycation End Products in CKD † ‡ ‡ Andréa E.M. Stinghen,* Ziad A. Massy,* Helen Vlassara, § Gary E. Striker, § and | Agnès Boullier* *Institut National de la Santé et de la Recherche Médicale (INSERM) U-1088, Jules Verne University of Picardie, Amiens, France; †Division of Nephrology, Ambroise Paré University Medical Center, Assistance Publique-Hôpitaux de Paris (APHP), University of Paris Ouest, University Versailles-Saint Quentin, Boulogne Billancourt/Paris, France; ‡Division of Experimental Diabetes and Aging, Departments of Geriatrics and Palliative Care and Medicine and §Division of Experimental Diabetes and Aging, Department of Geriatrics and Aging and Division of Nephrology, Department of Medicine, Icahn School of Medicine, New York, New York; and |Biochemistry Laboratory, Amiens University Medical Center, Amiens, France ABSTRACT Advanced glycation end products (AGEs), a heterogeneous group of compounds include the 1,2-dicarbonyl compounds formed by nonenzymatic glycation reactions between reducing sugars and amino glyoxal and methylglyoxal (MG), a highly acids, lipids, or DNA, are formed not only in the presence of hyperglycemia, but also in reactive dicarbonyl compound.7 At least diseases associated with high levels of oxidative stress, such as CKD. In chronic renal 20 different types of AGE have been de- failure, higher circulating AGE levels result from increased formation and decreased scribed: N-carboxymethyllysine (CML), renal clearance. Interactions between AGEs and their receptors, including advanced pentosidine, and hydroimidazolone are glycation end product–specific receptor (RAGE), trigger various intracellular events, among the best characterized, are rela- such as oxidative stress and inflammation, leading to cardiovascular complications. tively nonreactive, and serve as markers Although patients with CKD have a higher burden of cardiovascular disease, the re- ofAGEaccumulationinseveraltis- lationship between AGEs and cardiovascular disease in patients with CKD is not fully sues.8,9 AGEs can be degraded by en- characterized. In this paper, we review the various deleterious effects of AGEs in CKD zymes, such as glyoxalase I (Glo-1) and that lead to cardiovascular complications and the role of these AGEs in diabetic ne- II (Glo-2).10 Glo-1 detoxifies reactive phropathy. We also discuss potential pharmacologic approaches to circumvent these a-oxoaldehyde, removing deleterious deleterious effects by reducing exogenous and endogenous sources of AGEs, increas- species, such as MG.11 AGEs can also be ing the breakdown of existing AGEs, or inhibiting AGE-induced inflammation. Finally, modified by innate defense machineries, we speculate on preventive and therapeutic strategies that focus on the AGE-RAGE such as lysozyme, which sequesters AGEs axis to prevent vascular complications in patients with CKD. and accelerates their renal excretion in vivo,12 and receptor-dependent uptake J Am Soc Nephrol 27: 354–370, 2016. doi: 10.1681/ASN.2014101047 and degradation.13 Receptors for AGEs Advanced glycation end products (AGEs) formation of an unstable, freely reversible Advanced glycation end products receptor 1 constitute a heterogeneous group of com- Schiff base. This base can be rearranged to (AGER1) binds AGEs14 and leads to their pounds derived from the nonenzymatic form a more stable intermediate called an sequestration and detoxification, thus glycationofproteins,lipids,andnuclear Amadori product, which in the presence acids through a complex sequence of ofatransitionmetal,isoxidizedtoyieldthe reactionsreferredtoastheMaillard final AGE (Figure 1) (reviewed in ref. 3). Published online ahead of print. Publication date reaction.1,2 AGEs can also be formed by autoxida- available at www.jasn.org. tion of glucose and oxidative stress. Hu- Correspondence: Dr. Agnès Boullier, INSERM U-1088, Generation of AGEs mans are exposed to exogenous sources of Université de Picardie Jules Verne (UPJV), Centre Hos- pitalier Universitaire (CHU) Sud, Avenue Laënnec-Salouel, 4 5 Protein glycation is initiated by a nucle- AGE (diet and cigarette smoke )anden- F-80054 Amiens Cédex 1, France. Email: agnes. ophilic addition reaction between a free dogenous sources of AGE when the or- [email protected] aminogroupfromaproteinandacarbonyl ganism is exposed to high levels of glucose, Copyright © 2016 by the American Society of group from a reducing sugar, with the such as in diabetes.6 AGE precursors Nephrology 354 ISSN : 1046-6673/2702-354 J Am Soc Nephrol 27: 354–370, 2016 www.jasn.org BRIEF REVIEW proinflammatory chemokines. Signaling through full-length RAGE is known to be essential for both physiologic and path- ologic processes.8,24–27 sRAGE acts as a decoy for RAGE ligands and modulates activation or signaling through RAGE.28 PATHOPHYSIOLOGIC EFFECTS OF AGES Mechanisms Accumulation of AGEs in patients with CKD has been shown to result from inflammation, oxidative stress, and diet (Figure 2).29,30 AGEs are proinflamma- tory and pro-oxidative compounds that play a role in the high prevalence of en- dothelial dysfunction and subsequent cardiovascular disease (CVD) in patients with CKD.31 Figure 1. Main steps in AGE formation. Oxidative Stress The oxidative stress induced by reactive oxygen species (ROS) is associated with atherosclerosis and cardiovascular morbid- reducing AGE levels in the intracellular space, where it can sequester AGEs. ity in patients with CKD.32 AGEs increase and extracellular spaces, resulting in High sRAGE levels are associated with the levels of ROS33 through activation of antioxidant properties.15,16 Advanced an increased incidence of CKD before NADPH oxidase34 and mitochondrial glycation end product–specific receptor but not after adjustment for baseline kid- pathways in both a receptor-dependent (RAGE), another well characterized recep- ney function,21 suggesting that either cir- manner (i.e.,throughRAGE)35 and a tor for AGEs, is a multiligand transmem- culating sRAGE levels are directly affected receptor-independent manner. In patients brane cell surface receptor that belongs to by an impaired kidney filtration as as- with type 2 diabetes mellitus, circulating the Ig protein superfamily17,18 and binds sessed by GFR or inversely, circulating AGE levels are correlated with RAGE many ligands, including AGEs.19 In the sRAGE directly affects kidney function. mRNA expression and oxidative markers, absence of disease, RAGE is usually ex- Additional studies are needed to elucidate such as protein carbonyl formation, ad- pressed at very low levels in various cell the mechanisms of the association be- vanced oxidation protein product genera- types (smooth muscle cells, macrophages, tween sRAGE and kidney disease. tion, and lipid peroxidation.36 Reciprocally, and endothelial cells). In several dis- high levels of ROS lead to increased levels eases, such as diabetes and autoimmune/ Signaling through RAGE of AGEs,37 because another cause of AGE inflammatory diseases, RAGE expression RAGE was first identified as a signal formationinuremiaistheincreasedoxi- is elevated,20 whereas AGER1 levels are de- transduction receptor for AGEs linked to dative stress generated by an imbalance creased, resulting in suppression of the an- proteins or lipids.22 RAGE can also in- between oxidized glutathione and GSH tioxidant defense system and increased teract with advanced oxidation protein levels as well as changes in antioxidant levels of pro-oxidant mechanisms. The products, supporting the hypothesis systems, such as superoxide dismutase soluble truncated form of RAGE lacks that ligands generated by oxidative stress (SOD)/peroxidase.5 In fact, oxidative the full–length transmembrane domain may signal through RAGE.23 Full-length stress is closely linked to glycation, be- of the receptor. Soluble advanced glycation RAGE contains a single transmembrane cause GSH depletion also decreases the end product–specific receptor (sRAGE) region and a short intracellular domain. in situ activity of Glo-1, thereby increasing can be produced by alternative splicing Upon binding to RAGE, AGEs activate glyoxal and MG concentrations.10 Inter- (endogenous secretory advanced glycation several signaling pathways, including estingly, AGER1 is downregulated by ele- end product–specific receptor [esRAGE]) NF-kB, mitogen-activated protein kina- vated AGE levels.38 Furthermore, AGEs or proteolytic cleavage mediated by ses, and Jun N-terminal kinase, which in have been shown to increase the oxidation metalloproteinase (sRAGE). It is conse- turn, regulate the transcription of pro- of LDLs39—a key stage in the develop- quently released into the extracellular teins, such as adhesion molecules and ment of atherosclerosis.40 Glycated LDLs J Am Soc Nephrol 27: 354–370, 2016 Uremic Toxicity of AGEs in CKD 355 BRIEF REVIEW www.jasn.org Figure 2. Pathophysiologic effects of AGEs. cGMP, cyclic guanosine monophosphate; ECM, extracellular matrix; eNOS, endothelial NO 2 2 synthase; EPC, endothelial progenitor cell; O2 °, superoxide anion; ONOO , peroxynitrite. are, therefore, more susceptible to oxida- translocates to the nucleus to induce the Inflammation tion,41 are less effectively cleared from the expression of genes encoding antioxidant AGEs have been shown to amplify inflam- circulation, and also, promote the forma- and detoxifying molecules by binding to matory responses in patients with CKD50,51 tion of antibodies that bind AGEs local- the antioxidant response element region through RAGE,52,53 because the RAGE- ized in the