Ihm SH, Chang K, Kim HY, Baek SH, Youn HJ, Seung KB, Kim JH. The downstream consequences of the AGEs/RAGE axis involve compromised insulin signaling, perturbation of metabolic homeostasis, RAGE-induced pancreatic beta cell toxicity, and epigenetic modifications. 2015;5:194222. Posch K, Simecek S, Wascher TC, Jrgens G, Baumgartner-Parzer S, Kostner GM, Graier WF. Globulins make up 35% of plasma proteins and are used in the transport of ions, hormones and lipids assisting in immune function. Fluorescent cross-linking AGEs such as pentosidine and crossline. Kislinger T, Fu C, Huber B, Qu W, Taguchi A, Du Yan S, Hofmann M, Yan SF, Pischetsrieder M, Stern D, Schmidt AM. These pathologic processes may affect every cell component in peripheral nervous tissues. Stitt AW, Curtis TM. An AGE cross-link, pentosidine, is a sensitive and specific marker for tissue levels of AGEs. Giardino I, Edelstein D, Brownlee M. Nonenzymatic glycosylation in vitro and in bovine endothelial cells alters basic fibroblast growth factor activity. Bodiga VL, Eda SR, Bodiga S. Advanced glycation end products: role in pathology of diabetic cardiomyopathy. Federal government websites often end in .gov or .mil. The formation of advanced glycation end products appears to be enhanced in the diabetes as a result of hyperglycemia. Walton HA, Byrne J, Robinson GB. Although there are several lysine and arginine residues in the serum albumin structure, but very few of them can take part in the glycation reaction. Disease progression is also seen in the tubulointerstitial compartment causing expansion of tubular basement membranes, tubular atrophy, interstitial fibrosis and arteriosclerosis. Flier JS, Mueckler MM, Usher P, Lodish HF. Helen Vlassara; Receptor-Mediated Interactions of Advanced Glycosylation End Products With Cellular Components Within Diabetic Tissues. Binding to RAGE activates a variety of signaling pathways leading to increased oxidative stress and synthesis of local growth factors, cytokines and adhesion molecules [96]. Stefanska B. Curcumin ameliorates hepatic fibrosis in type 2 diabetes mellitus - insights into its mechanisms of action. The development of diabetic complications can be accelerated by AGEs. Wada R, Nishizawa Y, Yagihashi N, Takeuchi M, Ishikawa Y, Yasumura K, Nakano M, Yagihashi S. Effects of OPB-9195, anti-glycation agent, on experimental diabetic neuropathy. Smit AJ, Lutgers HL. The cells expressing high levels of the glucose transporter 1 (GLUT 1), such as vascular endothelial cells, are unable to regulate intracellular glucose concentrations and are more susceptible to hyperglycaemia-induced damage. In an early stage, sugars react with a free amino group to form Schiff base which undergoes a rearrangement to a more stable product known as amadori product. The role of glycated albumin in diabetic retinopathy has also been established [39]. On the other hand, the structural impairment in collagen alters the osteoblast differentiation leading to bone remodeling and skeletal fragility [8,9]. Some studies investigated the effects of the PPAR- agonist, rosiglitazone, on myocardial expression of RAGE, extent of cardiac fibrosis, and left ventricular (LV) diastolic function in experimental models of diabetes and found that RAGE play an important role in diabetic myocardial fibrosis [164]. Korean red ginseng extract alleviates advanced glycation end product-mediated renal injury. Unoki H, Yamagishi S. Advanced glycation end products and insulin resistance. AGEs play a pivotal role in loss of lens transparency, i.e., cataract development [109]. Moreover, AGEs can also act as cross-linkers between proteins, resulting in the production of proteinase-resistant aggregates [24]. In the lens AGEs induce irreversible changes in structural proteins, which lead to lens protein aggregation and formation of high-molecular-weight aggregates that scatter light and impede vision [90]. The pathogenic role of Maillard reaction in the aging eye. Crosslinking of proteins by AGE in the vessel wall increases vascular stiffness and modification of ECM proteins decreases pericyte adherence [94]. PMC In the late stage of the glycation process AGEs (irreversible compounds) are formed. AGE-modified extracellular proteins also cause retinal injury via binding to RAGE [95]. Zong H, Ward M, Stitt AW. AGEs often accumulate intracellularly [12] as a result of their generation from glucose-derived dicarbonyl pre cursors [13]. adducts of proteins that accumulate in vascular tissues with aging and at an accelerated rate in people with diabetes; AGEs are closely linked to tissue . Recently, it is evaluated that detoxification of MGOreduces AGEs accumulation which in turn can prevent formation of key retinal neuroglial and vascular lesions [88]. doi: 10.1007/PL00002934. Rother KI. Interaction of AGE with RAGE in the epithelium of the lens further increased the O2- and H2O2 generation [115]. AGEs progressively accumulate in the lens and retina to adversely affect the vision [90]. Advanced glycation endproducts: a biomarker for age as an outcome predictor after cardiac surgery? Sato K, Tatsunami R, Yama K, Tampo Y. Glycolaldehyde induces cytotoxicity and increases glutathione and multidrug-resistance-associated protein levels in Schwann cells. Cooper ME, Bonnet F, Oldfield M, Jandeleit-Dahm K. Mechanisms of diabetic vasculopathy: an overview. Diabetes and Advanced Glycoxidation End Products. Glycation also results in increased synthesis of type III collagen, 3(IV) collagen, type V collagen, type VI collagen, laminin, and fibronectin in the ECM, most likely via up-regulation of TGF- [179]. Formation of glyoxal, methylglyoxal and 3-deoxyglucosone in the glycation of proteins by glucose. Inclusion in an NLM database does not imply endorsement of, or agreement with, Recent results have shown that AGEs play an essential role in degenerative changes in lens and approaches towards utilizing low AGEs-content food may be beneficial to delay cataract formation [109]. The GLUT1 transporter, which is localized on the plasma membrane is thought to be a primary mediator of glucose uptake in the heart [167] and its expression is increased within hours of ischemia or induction of hypertrophy. In an intermediate stage, the amadori product degrades to a variety of reactive dicarbonyl compounds such as glyoxal, MGO, and deoxyglucosones via dehydration, oxidation and other chemical reactions. Insulin mediates the translocation of GLUT4 to the plasma membrane from a pool of intracellular vesicles and represents a critical control point by which the net flux of glucose is regulated. Advanced glycation end-products are proteins that become glycated after contact with sugars and are implicated in endothelial dysfunction and arterial stiffening. Ma H, Li SY, Xu P, Babcock SA, Dolence EK, Brownlee M, Li J, Ren J. AGEs bind only to the V domain of RAGE [70,71] and a sustained period of cellular activation mediated by receptor-dependent signaling, leads to inflammation. Sugimoto K, Nishizawa Y, Horiuchi S, Yagihashi S. Localization in human diabetic peripheral nerve of N(epsilon)-carboxymethyllysine-protein adducts, an advanced glycation endproduct. Fukami K, Yamagishi S, Kaifu K, Matsui T, Kaida Y, Ueda S, Takeuchi M, Asanuma K, Okuda S. Telmisartan inhibits AGE-induced podocyte damage and detachment. 2002;251:87-101. Retinopathy is a serious microvascular complication of diabetes and is the leading cause of blindness in individuals between the ages of 30 and 70 years [81,82] and is characterized by increased proliferation of blood vessels, vascular occlusion, angiogenesis, loss of pericytes from retinal capillaries, microaneurysms, haemorrhages increased retinal capillary permeability, thickening of the capillary basement membrane and infarction affecting the retina of the eye [81]. AGEs are toxic to AGE receptors possessing pericytes, and damage to pericytes is reported in diabetic retinopathy [97]. It is reported that nitric oxide (NO), a mediator for vasodilatation, is quenched by AGEs [158]. -, Mohammedi K., Woodward M., Marre M., Colagiuri S., Cooper M., Harrap S., Mancia G., Poulter N., Williams B., Zoungas S. Comparative Effects of Microvascular and Macrovascular Disease on the Risk of Major Outcomes in Patients with Type 2 Diabetes. Fibrin(ogen) may be an important target for methylglyoxal-derived AGE modification in elastic arteries of humans. Advanced glycation endproduct (AGE) accumulation and AGE receptor (RAGE) up-regulation contribute to the onset of diabetic cardiomyopathy. Pravastatin reduces tubular damage in diabetic nephropathy by inhibiting ADMA generation in tubular cells and attenuating AGEs-induced apoptosis [125]. Glycated IgG is associated with inflammation and is a target for auto-antibodies in rheumatoid arthritis patients [52]. Both type-1 and type-2 diabetes are powerful and independent risk factors for coronary artery disease, . In vitro experiment demonstrated that oxidative stress enhances glycation of Na+ K+-ATPase (when incubated with glucose) to reduce the activity [157]. government site. Stitt AW. Epub 2020 Jul 28. The pattern recognition receptor (RAGE) is a counterreceptor for leukocyte integrins: a novel pathway for inflammatory cell recruitment. The results indicate that glycation of Na+ K+-ATPase may play a role in the reduction in motor nerve conduction velocity as often detected in diabetic human patients and animal models. Kikuchi S, Shinpo K, Takeuchi M, Yamagishi S, Makita Z, Sasaki N, Tashiro K. Glycation--a sweet tempter for neuronal death. Would you like email updates of new search results? AGEs, RAGE, and diabetic retinopathy. Metal catalyzed autooxidation of glucose (Wolff pathway) or reverse aldol reaction and autooxidation of the Schiff base (Namiki pathway) or non-oxidative Amadori product cleavage (Hodge pathway) forms reactive dicarbonyls and AGEs precursors that contribute significantly to AGEs formation. This excessive cross-linking disturbs the flexibility characteristic of matrix proteins, making them rigid. The AGEs/RAGE/NFB-driven sustained inflammation and oxidative stress activation of signaling cascades play an important role in the pathogenesis of diabetic complications. Protein glycation and formation of advanced glycation end products (AGEs) play an important role in the pathogenesis of diabetic complications like retinopathy, nephropathy, neuropathy, cardiomyopathy along with some other diseases such as rheumatoid arthritis, osteoporosis and aging. N(epsilon)-(carboxymethyl)lysine adducts of proteins are ligands for receptor for advanced glycation end products that activate cell signaling pathways and modulate gene expression. Receptor for advanced glycation endproducts (RAGE) and the complications of diabetes. This upregulation of RAGE may cause an increase in transduction signals following stimulation by AGEs and this may exacerbate loss of pericytes in diabetic retinopathy. Taegtmeyer H. Energy metabolism of the heart: from basic concepts to clinical applications. In an early stage, glucose (or other reducing sugars such as fructose, pentoses, galactose, mannose, xylulose) react with a free amino group of biological amines to form an unstable compound, the Schiff base which undergoes a rearrangement to a more stable product known as amadori product [22]. Neeper M, Schmidt AM, Brett J, Yan SD, Wang F, Pan YC, Elliston K, Stern D, Shaw A. Cloning and expression of a cell surface receptor for advanced glycosylation end products of proteins. Williams SK, Howarth NL, Devenny JJ, Bitensky MW. The AGEs are yellow-brown, fluorescent and insoluble adducts that accumulate on long-lived proteins thus impair their physiological functions [23]. Thornalley PJ, Langborg A, Minhas HS. Baynes JW, Thorpe SR. Role of oxidative stress in diabetic complications: a new perspective on an old paradigm. In contrast to the Amadori product, which is in equilibrium with glucose, AGE is irreversibly attached to the proteins. Alterations in human glomerular epithelial cells interacting with nonenzymatically glycosylated matrix. It is demonstrated that AGEs could induce podocyte DNA damage and detachment partly via stimulation of the angiotensin II (Ang II) type 1 receptor (AT1R) [128]. The potential clinical application of RAGE blockade include the decreased progression of diabetic retinopathy as upregulation of RAGE leads to pro-inflammatory responses by retinal Mller glia cells [83]. J Intern Med. We aimed to investigate the relationships between advanced glycation end-products, measured as skin autofluorescence, and vascular stiffness in various glycemic strata. Bauer S, Hezinger L, Rexhepi F, Ramanathan S, Kufer TA. 2023 May 13;12(10):1383. doi: 10.3390/cells12101383. In the late stage of glycation, irreversible compoundscalled AGEs are formed through oxidation, dehydration and cyclization reactions. Neviere R, Yu Y, Wang L, Tessier F, Boulanger E. Glycoconj J. Protein glycation reactions leading to AGEs are thought to be the major causes of different diabetic complications [5]. Furthermore, the role of AGEs in the pathogenesis of diabetic complications including retinopathy, cataract, neuropathy, nephropathy and cardiomyopathy is also discussed. Collagen is a major component of the ECM and is a prominent target of non-enzymatic glycation [53]. However, glycation of fibrinogen has been reported to impair fibrinolysis [45] and increase fibrin gel permeability, resulting in formation of a less thrombogenic fibrin network [46]. Some studies revealed that Mller glial dysfunction during diabetic retinopathy in rats is linked to accumulation of AGEs [86]. RAGE is composed of three extracellular domains, which include a V-type that possesses ligand binding properties and two C-type immunoglobulin domains C 1, and C 2, a trans membrane helix and a short cytosolic tail [69]. The amino groups of adenine and guanine bases in DNA are also susceptible to glycation and AGE formation [21]. The levels of VEGF in ocular fluid correlate with the activity of neovascularisation in retinopathy and are also associated with the breakdown of the blood-retinal barrier which may be involved in the increased microvascular permeability seen in retinopathy. The role of advanced glycation end products in retinal microvascular leukostasis. It has been used as the model protein for physical biochemists because of its ease of purification. Advanced glycosylation end products stimulate collagen mRNA synthesis in mesangial cells mediated by protein kinase C and transforming growth factor-beta. Role of receptor for advanced glycation end-product (RAGE) and the JAK/STAT-signaling pathway in AGE-induced collagen production in NRK-49F cells. Vlassara H, Li YM, Imani F, Wojciechowicz D, Yang Z, Liu FT, Cerami A. Han D, Yamamoto Y, Munesue S, Motoyoshi S, Saito H, Win MT, Watanabe T, Tsuneyama K, Yamamoto H. Induction of receptor for advanced glycation end products by insufficient leptin action triggers pancreatic -cell failure in type 2 diabetes. Oldfield MD, Bach LA, Forbes JM, Nikolic-Paterson D, McRobert A, Thallas V, Atkins RC, Osicka T, Jerums G, Cooper ME. O'Connor AS, Schelling JR. Diabetes and the kidney. Lund T, Svindland A, Pepaj M, Jensen AB, Berg JP, Kilhovd B, Hanssen KF. Yamagishi S, Hsu CC, Taniguchi M, Harada S, Yamamoto Y, Ohsawa K, Kobayashi K, Yamamoto H. Receptor-mediated toxicity to pericytes of advanced glycosylation end products: a possible mechanism of pericyte loss in diabetic microangiopathy. A group of chemical compounds are generated that appears to activate the intracellular signaling pathways and generation of proinflammatory and prosclerotic cytokines which further leads to the development and progression of diabetic complications. Large proportion of plasma proteins has circulating half lives in human 1~2 weeks [34]. Helou C, Marier D, Jacolot P, Abdennebi-Najar L, Niquet-Lridon C, Tessier FJ, Gadonna-Widehem P. Microorganisms and Maillard reaction products: a review of the literature and recent findings. In this review, we revisit the role played by AGEs in CVD based in clinical trials and experimental evidence. The engagement of AGEs with its chief cellular receptor, RAGE, activates a myriad of signaling pathways such as MAPK/ERK, TGF-, JNK, and NF-B, leading to enhanced oxidative stress and inflammation. Epub 2018 Jun 5. 2006) (Fig. Diabetes Res. Interaction of metabolic and haemodynamic factors in mediating experimental diabetic nephropathy. Throckmorton DC, Brogden AP, Min B, Rasmussen H, Kashgarian M. PDGF and TGF-beta mediate collagen production by mesangial cells exposed to advanced glycosylation end products. Renal disease in diabetic patients is characterized by haemodynamic (hyperfiltration and hyperperfusion) as well as structural abnormalities (glomerulosclerosis, alterations in tubulointerstitium including interstitial fibrosis) and metabolic changes [124]. Vasan S, Foiles P, Founds H. Therapeutic potential of breakers of advanced glycation end product-protein crosslinks. Diabetologia. Lagadic-Gossmann D, Buckler KJ, Le Prigent K, Feuvray D. Altered Ca, Trost SU, Belke DD, Bluhm WF, Meyer M, Swanson E, Dillmann WH. This protein is the longest living protein in higher animals, where it occurs primarily as extracellular, insoluble fibers. Advanced glycation end products stimulate osteoblast apoptosis via the MAP kinase and cytosolic apoptotic pathways. Tanabe N, Tomita K, Manaka S, Ichikawa R, Takayama T, Kawato T, Ono M, Masai Y, Utsu A, Suzuki N, Sato S. Cells. RAGE binds with these toxic IAPP intermediates and leads to the formation of amyloid plaque resulting in pancreatic beta cell toxicity. The site is secure. RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides. Halliwell B. 1 Altmetric Metrics Abstract Little is known about advanced glycation end products (AGEs) participation in glucose homeostasis, a process in which skeletal muscle glucose transporter GLUT4 (. 2023 Jun 21;12(13):1684. doi: 10.3390/cells12131684. El-Mesallamy HO, Hamdy NM, Ezzat OA, Reda AM. Vlassara H, Brownlee M, Cerami A. Nonenzymatic glycosylation of peripheral nerve protein in diabetes mellitus. Albuminuria and glomerular filtration rate used to assess kidney function are considered surrogate outcomes of chronic kidney disease. Zhou J, Chan L, Zhou S. Trigonelline: a plant alkaloid with therapeutic potential for diabetes and central nervous system disease. Formation of advanced glycation end products in three stages i.e., early, intermediate and late stage involving (AGEs). Upon entry into the cells, free glucose is rapidly phosphorylated by hexokinase to form glucose-6-phosphate (G-6-P), trapping glucose inside the cell. AGEs, however, increase the degree of cross-linking over the basal physiological levels, with matrix proteins such as collagen, laminin, vitronectin, and elastin [174]. [2] Dietary sources The role of advanced glycation in the pathogenesis of diabetic retinopathy. Valcourt U, Merle B, Gineyts E, Viguet-Carrin S, Delmas PD, Garnero P. Non-enzymatic glycation of bone collagen modifies osteoclastic activity and differentiation. Received 2013 Jul 24; Revised 2013 Oct 11; Accepted 2013 Dec 10. Because RAGE is expressed in the endothelial cells of peri- and endoneurial blood vessels, it is assumed that the interaction between AGEs and RAGE on the endothelial cells plays a role in the development of peripheral neuropathy [160]. Diabetes is the leading cause of end-stage kidney disease (ESKD) since 30-40% of diabetic patients develop diabetic nephropathy. A fourth trans membrane domain anchors RAGE in the membrane and is connected to a highly charged fifth intracellular domain that mediates interaction with cytosolic transduction molecules. The elevated levels of glucose starts forming covalent adducts with plasma proteins through a non-enzymatic process known as glycation. Sohn E, Kim J, Kim CS, Lee YM, Jo K, Shin SD, Kim JH, Kim JS.