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• W2788736028 abstract "Advanced glycation end products (AGEs) are stable posttranslational 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 metabolized by glyoxalase 1 (Glo1) of the cytoplasmic glyoxalase system. Proteins susceptible to MG modification are collectively called the dicarbonyl proteome. Abnormal increase of MG dicarbonyl stress 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 demonstrated a profound improvement in insulin resistance and vascular inflammation. It may find future therapeutic application for treatment of DKD. Advanced glycation end products (AGEs) are stable posttranslational 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 metabolized by glyoxalase 1 (Glo1) of the cytoplasmic glyoxalase system. Proteins susceptible to MG modification are collectively called the dicarbonyl proteome. Abnormal increase of MG dicarbonyl stress 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 demonstrated a profound improvement in insulin resistance and vascular inflammation. It may find future therapeutic application for treatment of DKD. Advanced glycation end products (AGEs) are a group of compounds formed by the nonenzymatic reaction of reducing sugars and related metabolites with proteins and amino acids. The process is called glycation or the Maillard reaction. Major precursors of AGEs in vivo are the early-stage glycation adduct Nε-fructosyl-lysine (FL) and dicarbonyl metabolites methylglyoxal (MG), glyoxal, and 3-deoxyglucosone (3-DG).1Thornalley P.J. Rabbani N. Detection of oxidized and glycated proteins in clinical samples using mass spectrometry - a user's perspective.Biochim Biophys Acta. 2014; 1840: 818-829Crossref PubMed Scopus (46) Google Scholar Major AGEs quantitatively are MG-derived hydroimidazolone (MG-H1) and FL-derived Nε-carboxymethyl-lysine (CML) and the cross-link glucosepane (Figure 1). AGEs are formed as glycated amino acid residues of proteins, which are conventionally called AGE residues of proteins, although they are often called protein-bound AGEs in renal research. AGE-modified proteins are degraded to related glycated amino acids, called AGE free adducts. AGEs are also formed from glucose osmolyte, MG, and other glucose degradation product dicarbonyls absorbed from thermally processed dialysis fluids in renal replacement therapy. AGEs may also be absorbed from glycated proteins in food, mainly as AGE free adducts. AGEs may be quantified robustly by stable isotopic dilution analysis liquid chromatography and tandem mass spectrometry (LC-MS/MS).1Thornalley P.J. Rabbani N. Detection of oxidized and glycated proteins in clinical samples using mass spectrometry - a user's perspective.Biochim Biophys Acta. 2014; 1840: 818-829Crossref PubMed Scopus (46) Google Scholar AGEs represent relatively long-lived and potentially damaging posttranslational modification of proteins. They are mostly damaging through modification of functional domains of proteins, producing protein inactivation or dysfunction. Herein we review evidence of protein-derived AGEs. There are also AGEs formed by MG and glyoxal modification of nucleotides and basic phospholipids, phosphatidylethanolamine and phosphatidylserine.2Thornalley P.J. Waris S. Fleming T. et al.Imidazopurinones are markers of physiological genomic damage linked to DNA instability and glyoxalase 1-associated tumour multidrug resistance.Nucleic Acids Res. 2010; 38: 5432-5442Crossref PubMed Scopus (42) Google Scholar, 3Requena J.R. Ahmed M.U. Fountain C.W. et al.Carboxymethylethanolamine, a biomarker of phospholipid modification during the Maillard reaction in vivo.J Biol Chem. 1997; 272: 17473-17479Crossref PubMed Scopus (75) Google Scholar These have been little-studied in chronic kidney disease (CKD),4Waris S. Winklhofer-Roob B.M. Roob J.M. et al.Increased DNA dicarbonyl glycation and oxidation markers in patients with type 2 diabetes and link to diabetic nephropathy.J Diabetes Res. 2015; 2015: 10Crossref Scopus (6) Google Scholar and so the coverage below focuses on protein-derived AGEs. The formation of AGEs is suppressed by enzymatic metabolism of the precursor glycating agents or glycation adduct FL. MG and glyoxal are metabolized mainly by the cytoplasmic glyoxalase system. The glyoxalase system consists of 2 enzymes, glyoxalase 1 (Glo1) and glyoxalase 2, and a catalytic amount of reduced glutathione (GSH). Glo1 catalyzes the GSH-dependent metabolism of MG to S-D-lactoylglutathione, and glyoxalase 2 catalyzes the hydrolysis of S-D-lactoylglutathione to D-lactate, reforming GSH consumed in the Glo1 catalyzed step5Rabbani N. Thornalley P.J. Dicarbonyls (glyoxal, methylglyoxal, and 3-deoxyglucosone).in: Niwa T. Uremic Toxins. John Wiley & Sons Inc., Hoboken, NJ2012: 177-192Crossref Scopus (19) Google Scholar (Figure 2). 3-DG and likely also 3,4-dideoxyglucosone-3-ene (3,4-DGE) found in thermally processed peritoneal dialysis (PD) fluids with glucose osmolyte are metabolized by aldoketo reductases (AKRs) and aldehyde dehydrogenases. The kidney has a very high activity of aldose reductase, approximately 2% total protein, in the inner medulla that primarily reduces glucose to sorbitol to counter high extracellular osmotic pressure.6Nishimura C. Furue M. Ito T. et al.Quantitative determination of human aldose reductase by enzyme-linked immunosorbent assay.Biochem Pharmac. 1993; 46: 21-28Crossref PubMed Scopus (31) Google Scholar Steady-state levels of FL residues are suppressed by enzymatic metabolism by fructosamine-3-phosphokinase, resulting in deglycation of precursor lysine residues.1Thornalley P.J. Rabbani N. Detection of oxidized and glycated proteins in clinical samples using mass spectrometry - a user's perspective.Biochim Biophys Acta. 2014; 1840: 818-829Crossref PubMed Scopus (46) Google Scholar Dicarbonyl stress is the abnormal accumulation of MG and related dicarbonyl compounds, leading to increased AGE formation and related cell and tissue dysfunction. Dicarbonyl stress is a driver of CKD development, as evidenced by development of nephropathy in Glo1-deficient mice.7Giacco F. Du X. D’Agati V.D. et al.Knockdown of glyoxalase 1 mimics diabetic nephropathy in nondiabetic mice.Diabetes. 2014; 63: 291-299Crossref PubMed Scopus (52) Google Scholar Dicarbonyl stress may also be consequence of renal failure, as evidenced by dicarbonyl stress with loss of clearance in bilateral nephrectomized rats.8Rabbani N. Sebekova K. Sebekova Jr., K. et al.Protein glycation, oxidation and nitration free adduct accumulation after bilateral nephrectomy and ureteral ligation.Kidney Int. 2007; 72: 1113-1121Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar Dicarbonyl stress occurs in patients with CKD,5Rabbani N. Thornalley P.J. Dicarbonyls (glyoxal, methylglyoxal, and 3-deoxyglucosone).in: Niwa T. Uremic Toxins. John Wiley & Sons Inc., Hoboken, NJ2012: 177-192Crossref Scopus (19) Google Scholar including accumulation of MG without increase in D-lactate in nondiabetic subjects.9Ficek J. Wyskida K. Ficek R. et al.Relationship between plasma levels of zonulin, bacterial lipopolysaccharides, d-lactate and markers of inflammation in haemodialysis patients.Int Urol Nephrol. 2017; 49: 717-725Crossref PubMed Scopus (3) Google Scholar D-Lactate is a marker of flux of formation of MG.10Rabbani N. Xue M. Thornalley P.J. Methylglyoxal-induced dicarbonyl stress in aging and disease: first steps towards glyoxalase 1-based treatments.Clin Sci (Lond). 2016; 130: 1677-1696Crossref PubMed Google Scholar This suggests that the driver of dicarbonyl stress in CKD is down-regulation of Glo1 rather than increased formation of MG in nondiabetic subjects. Decreased urinary excretion of MG is not a major contributing factor because little MG is excreted, although this may be more important for 3-DG.10Rabbani N. Xue M. Thornalley P.J. Methylglyoxal-induced dicarbonyl stress in aging and disease: first steps towards glyoxalase 1-based treatments.Clin Sci (Lond). 2016; 130: 1677-1696Crossref PubMed Google Scholar Down-regulation of Glo1 in the kidney is a common feature of experimental diabetic nephropathy and diabetic kidney disease (DKD). It may be driven by decreased Glo1 expression in response to hypoxia-inducible factor-1α and inflammatory signaling conflicting with transcription factor Nrf2, and by increased proteolysis. Overexpression of Glo1 prevented renal senescence11Ikeda Y. Inagi R. Miyata T. et al.Glyoxalase I retards renal senescence.Am J Pathol. 2011; 179: 2810-2821Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar and development of diabetic nephropathy,7Giacco F. Du X. D’Agati V.D. et al.Knockdown of glyoxalase 1 mimics diabetic nephropathy in nondiabetic mice.Diabetes. 2014; 63: 291-299Crossref PubMed Scopus (52) Google Scholar, 12Brouwers O. Niessen P.M.G. Miyata T. et al.Glyoxalase-1 overexpression reduces endothelial dysfunction and attenuates early renal impairment in a rat model of diabetes.Diabetologia. 2014; 57: 224-235Crossref PubMed Scopus (44) Google Scholar the latter even when only in endothelial and tubular epithelial cells.7Giacco F. Du X. D’Agati V.D. et al.Knockdown of glyoxalase 1 mimics diabetic nephropathy in nondiabetic mice.Diabetes. 2014; 63: 291-299Crossref PubMed Scopus (52) Google Scholar This suggests that reversing renal down-regulation of Glo1 may provide a new route to therapy.10Rabbani N. Xue M. Thornalley P.J. Methylglyoxal-induced dicarbonyl stress in aging and disease: first steps towards glyoxalase 1-based treatments.Clin Sci (Lond). 2016; 130: 1677-1696Crossref PubMed Google Scholar The flux of MG formation in a healthy adult human subject is approximately 3 mmol MG per 24 hours, and >99% is normally metabolized enzymatically. MG concentration of PD fluids, 2 to 7 μM, is therefore not a major increment to MG exposure. For 3-DG, the flux of formation is approximately 0.13 mmol 3-DG per 24 hours, and approximately 90% is normally metabolized enzymatically with approximately 10% excreted. PD fluids containing 100 to 400 μM 3-DG increase exposure to 3-DG markedly, although 3-DG has approximately 200-fold lower reactivity than MG in protein glycation.5Rabbani N. Thornalley P.J. Dicarbonyls (glyoxal, methylglyoxal, and 3-deoxyglucosone).in: Niwa T. Uremic Toxins. John Wiley & Sons Inc., Hoboken, NJ2012: 177-192Crossref Scopus (19) Google Scholar, 10Rabbani N. Xue M. Thornalley P.J. Methylglyoxal-induced dicarbonyl stress in aging and disease: first steps towards glyoxalase 1-based treatments.Clin Sci (Lond). 2016; 130: 1677-1696Crossref PubMed Google Scholar AGE free adducts are the major form by which AGEs are eliminated from the body. Decreased clearance in CKD markedly influences the plasma concentrations of AGE free adducts.8Rabbani N. Sebekova K. Sebekova Jr., K. et al.Protein glycation, oxidation and nitration free adduct accumulation after bilateral nephrectomy and ureteral ligation.Kidney Int. 2007; 72: 1113-1121Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar, 13Agalou S. Ahmed N. Babaei-Jadidi R. et al.Profound mishandling of protein glycation degradation products in uremia and dialysis.J Am Soc Nephrol. 2005; 16: 1471-1485Crossref PubMed Scopus (89) Google Scholar The increase of AGE free adducts in clinical renal failure, studied in patients receiving hemodialysis (HD) and PD renal replacement therapy was 4- to 40-fold, whereas the increase in AGE residues of plasma protein was 2- to 5-fold.13Agalou S. Ahmed N. Babaei-Jadidi R. et al.Profound mishandling of protein glycation degradation products in uremia and dialysis.J Am Soc Nephrol. 2005; 16: 1471-1485Crossref PubMed Scopus (89) Google Scholar Drivers of AGE free adduct accumulation are increased flux of formation of AGEs and decreased clearance. The flux of formation of AGEs is indicated by the total excretion of AGE free adducts in dialysate and urine. In PD patients, flux of AGE formation was increased markedly with respect to healthy controls: 9-fold for MG-H1 and 2-fold for CML, pentosidine, and 3-DG-derived hydroimidazolones 3DG-H. The flux of excretion of MG-H1 free adduct in PD patients was 4- to 713-fold higher than of other AGEs, indicating MG-H1 is a dominant AGE in renal failure.13Agalou S. Ahmed N. Babaei-Jadidi R. et al.Profound mishandling of protein glycation degradation products in uremia and dialysis.J Am Soc Nephrol. 2005; 16: 1471-1485Crossref PubMed Scopus (89) Google Scholar AGE residue contents of plasma protein have been studied as biomarkers of mortality risk in renal failure with contrary outcomes or low marginal increased relative risk.14Schwedler S.B. Metzger T. Schinzel R. et al.Advanced glycation end products and mortality in hemodialysis patients.Kidney Int. 2002; 62: 301-310Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar, 15Wagner Z. Molnar M. Molnar G.A. et al.Serum carboxymethyllysine predicts mortality in hemodialysis patients.Am J Kidney Dis. 2006; 47: 294-300Abstract Full Text Full Text PDF PubMed Google Scholar Plasma protein AGEs, such as MG-H1 and 3DG-H, may be increased by dicarbonyl stress;13Agalou S. Ahmed N. Babaei-Jadidi R. et al.Profound mishandling of protein glycation degradation products in uremia and dialysis.J Am Soc Nephrol. 2005; 16: 1471-1485Crossref PubMed Scopus (89) Google Scholar CML and glucosepane may be increased by elevated FL residue precursor and/or decreased FL metabolism;16Monnier V.M. Sell D.R. Strauch C. et al.The association between skin collagen glucosepane and past progression of microvascular and neuropathic complications in type 1 diabetes.J Diabetes Complications. 2013; 27: 141-149Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar, 17Ahmed M.U. Thorpe S.R. Baynes J.W. Identification of Nε-carboxymethyl-lysine as a degradation product of fructoselysine in glycated protein.J Biol Chem. 1986; 261: 4889-4894PubMed Google Scholar, 18Biemel K.M. Friedl D.A. Lederer M.O. Identification and quantification of major Maillard cross-links in human serum albumin and lens protein - Evidence for glucosepane as the dominant compound.J Biol Chem. 2002; 277: 24907-24915Crossref PubMed Scopus (146) Google Scholar and pentosidine residue content may be increased by elevated pentosephosphate pathway activity providing increased level of the pentose precursor.19Wang F. Zhao Y. Niu Y. et al.Activated glucose-6-phosphate dehydrogenase is associated with insulin resistance by upregulating pentose and pentosidine in diet-induced obesity of rats.HormMetab Res. 2012; 44: 938-942Google Scholar AGE residue content of plasma protein is also influenced by decreased residence time of albumin in the vascular compartment by albuminuria,20Rabbani N. AntonySunil A. Rossing K. et al.Effect of Irbesartan treatment on plasma and urinary protein glycation, oxidation and nitration markers in patients with type 2 diabetes and microalbuminuria.Amino Acids. 2011; 42: 1627-1639Crossref PubMed Scopus (11) Google Scholar increased transcapillary escape rate influenced by hypertension and atherosclerosis,21Masania J. Malczewska-Malec M. Razny U. et al.Dicarbonyl stress in clinical obesity.Glycoconjugate J. 2016; 33: 581-589Crossref PubMed Scopus (4) Google Scholar and also by decreased albumin synthesis and catabolism.22Ahmed N. Thornalley P.J. Luthen R. et al.Processing of protein glycation, oxidation and nitrosation adducts in the liver and the effect of cirrhosis.J Hepatol. 2004; 41: 913-919Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar These confounders suggest that AGE residue content of plasma protein has a complex relationship with clinical outcomes in CKD. An indication of increased AGE formation in the kidney may be gained by measuring total body flux of formation of AGEs, or surrogate measures thereof, such as urinary or dialysate flux of AGE free adducts, plasma AGE free adduct concentration corrected for decline in glomerular filtration rate (GFR) in CKD stages G1 to G4, and plasma AGE free adduct concentration immediately prior to a dialysis session in HD patients or dialysis fluid exchange in PD patients. Correction may be made for contributions from food AGEs (see below). In a large cross-sectional study, increased serum CML measured by a competitive immunoassay was associated with CKD and negatively associated with GFR.23Semba R.D. Fink J.C. Sun K. et al.Serum carboxymethyl-lysine, a dominant advanced glycation end product, is associated with chronic kidney disease: the Baltimore Longitudinal Study of Aging.J Ren Nutr. 2010; 20: 74-81Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar The immunoassay used measured both serum protein CML residues and CML free adduct concurrently.24Zhang X. Frischmann M. Kientsch-Engel R. et al.Two immunochemical assays to measure advanced glycation end-products in serum from dialysis patients.Clin Chem Lab Med. 2005; 43: 503Crossref PubMed Scopus (45) Google Scholar CML free adduct is most sensitive to loss of renal clearance,8Rabbani N. Sebekova K. Sebekova Jr., K. et al.Protein glycation, oxidation and nitration free adduct accumulation after bilateral nephrectomy and ureteral ligation.Kidney Int. 2007; 72: 1113-1121Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar so such immunoassay formats may be reflecting accumulation of CML free adduct. Total plasma AGEs—the sum of AGE residues of protein and AGE-free adduct of selected types of plasma—have been determined by analysis of acid hydrolysates of plasma. Total plasma CML and CEL were increased in patients with type 1 diabetes and decreased GFR compared with those with normal GFR, and were linked to markers of endothelial cell dysfunction—von Willebrand factor, soluble vascular cellular adhesion molecule-1 (sVCAM1), and soluble thrombomodulin—independent of GFR.25Lieuw A.F. van Hinsbergh V.W.M. Teerlink T. et al.Increased levels of Nî-(carboxymethyl)lysine and Nî-(carboxyethyl)lysine in type 1 diabetic patients with impaired renal function: correlation with markers of endothelial dysfunction.Nephrol Dial Transplant. 2004; 19: 631-636Crossref PubMed Scopus (57) Google Scholar Total plasma pentosidine was a risk predictor of mortality in CKD after adjusting for all confounders.26Machowska A. Sun J. Qureshi A.R. et al.Plasma pentosidine and its association with mortality in patients with chronic kidney disease.PLoS One. 2016; 11: e0163826Crossref PubMed Scopus (1) Google Scholar In recent studies of AGEs and related analysis of skin collagen in patients with type 1 diabetes, an analyte panel of glucosepane, MG-H1, CML, Nε(1-carboxyethyl)lysine (CEL), glyoxal-derived hydroimidazolone (G-H1), pentosidine, furosine, collagen fluorescence, skin collagen acid solubility, and pepsin digestibility was linked to risk of progression of diabetic nephropathy, with the FL-linked analyte furosine being the strongest predictor.27Genuth S. Sun W. Cleary P. et al.Skin advanced glycation endproducts (AGEs) glucosepane and methylglyoxal hydroimidazolone are independently associated with long-term microvascular complication progression of type I diabetes.Diabetes. 2015; 64: 266-278Crossref PubMed Scopus (35) Google Scholar In contrast, CML residue content of plasma protein was not linked to the risk of developing diabetic nephropathy.28Klein R. Horak K. Lee K.E. et al.The relationship of serum soluble receptor for advanced glycation end products (sRAGE) and carboxymethyl lysine (CML) to the incidence of diabetic nephropathy in persons with type 1 diabetes.Diabetes Care. 2017; 40: e117-e119Crossref PubMed Scopus (0) Google Scholar Plasma MG-H1 free adduct concentration was an independent risk predictor for progression of DKD.29Beisswenger P.J. Howell S.K. Russell G.B. et al.Early Progression of diabetic nephropathy correlates with methylglyoxal-derived advanced glycation end products.Diabetes Care. 2013; 36: 3234-3239Crossref PubMed Scopus (43) Google Scholar Low molecular weight AGE fluorophore measurement was a mortality predictor in HD patients.30Roberts M.A. Thomas M.C. Fernando D. et al.Low molecular weight advanced glycation end products predict mortality in asymptomatic patients receiving chronic haemodialysis.Nephrol Dial Transplant. 2006; 21: 1611-1617Crossref PubMed Scopus (27) Google Scholar Skin autofluorescence (SAF) has been proposed as an noninvasive measure linked to the dermal content of AGEs.31Meerwaldt R. Graaff R. Oomen P.H.N. et al.Simple non-invasive assessment of advanced glycation endproduct accumulation.Diabetologia. 2004; 47: 1324-1330Crossref PubMed Google Scholar Spectrofluorometric analysis and scanning confocal microscopy and multi-photon excitation microscopy found that major contributions to SAF are from NAD(P)H, flavin adenine dinucleotide, and porphyrins.32Na R.H. Stender I.M. Ma L.X. et al.Autofluorescence spectrum of skin: component bands and body site variations.Skin Res Technol. 2000; 6: 112-117Crossref PubMed Scopus (71) Google Scholar, 33Masters B.R. So P.T.C. Confocal microscopy and multi-photon excitation microscopy of human skin in vivo.Opt Express. 2001; 8: 2-10Crossref PubMed Google Scholar There are also contributions from the oxidative fluorophore, N-formylkynurenine, and trace fluorescent AGEs such as pentosidine and others.31Meerwaldt R. Graaff R. Oomen P.H.N. et al.Simple non-invasive assessment of advanced glycation endproduct accumulation.Diabetologia. 2004; 47: 1324-1330Crossref PubMed Google Scholar Weaknesses of this approach are that SAF has important non-AGE contributions, and the major quantitative AGEs in CKD, MG-H1, and CML are not fluorescent. Change in SAF is likely reflecting a combination of metabolic dysfunction and protein-derived fluorophores in CKD. In assessment of risk of progression of CKD, an optimum cut-off level of SAF yielded sensitivity 0.74 and specificity of 0.73 for CKD progression,34Tanaka K. Nakayama M. Kanno M. et al.Skin autofluorescence is associated with the progression of chronic kidney disease: a prospective observational study.PLoS One. 2013; 8: e83799Crossref PubMed Scopus (17) Google Scholar and SAF was also linked to mortality risk in renal failure.35Meerwaldt R. Hartog J.W.L. Graaff R. et al.Skin autofluorescence, a measure of cumulative metabolic stress and advanced glycation end products, predicts mortality in hemodialysis patients.J Am Soc Nephrol. 2005; 16: 3687-3693Crossref PubMed Scopus (195) Google Scholar It was proposed that AGE-modified proteins bind specifically to cell surface receptors to activate cell dysfunction. This was questioned and considered limited to proteins structurally damaged and/or glycated to high, supraphysiological extents prepared in vitro.36Thornalley P.J. Cell activation by glycated proteins. AGE receptors, receptor recognition factors and functional classification of AGEs.Cell Mol Biol. 1998; 44: 1013-1023PubMed Google Scholar, 37Thornalley P.J. Dietary AGEs and ALEs and risk to human health by their interaction with the receptor for advanced glycation endproducts (RAGE) - an introduction.Mol Nutr Food Res. 2007; 51: 1107-1110Crossref PubMed Scopus (43) Google Scholar An AGE receptor found influential on the development of experimental diabetic nephropathy and DKD is the receptor for advanced glycation end products (RAGE). Transgenic mice overexpressing RAGE showed glomerular hypertrophy, increased albuminuria, mesangial expansion, advanced glomerulosclerosis, and increased serum creatinine compared to nontransgenic diabetic littermates.38Yamamoto Y. Kato I. Doi T. et al.Development and prevention of advanced diabetic nephropathy in RAGE-overexpressing mice.J Clin Invest. 2001; 108: 261-268Crossref PubMed Google Scholar RAGE-deficient mice show decreased albuminuria, hyperfiltration, and glomerulosclerosis compared with diabetic wild-type controls.39Sourris K.C. Morley A.L. Koitka A. et al.Receptor for AGEs (RAGE) blockade may exert its renoprotective effects in patients with diabetic nephropathy via induction of the angiotensin II type 2 (AT2) receptor.Diabetologia. 2010; 53: 2442-2451Crossref PubMed Scopus (38) Google Scholar RAGE expression is increased in peripheral blood monocytes in clinical CKD.40Hou F.F. Ren H. Owen W.F. et al.Enhanced expression of receptor for advanced glycation end products in chronic kidney disease.J Am Soc Nephrol. 2004; 15: 1889-1896Crossref PubMed Scopus (77) Google Scholar The use of albumin highly glycated by AGEs, dissimilar from albumin that is minimally modified by AGEs in vivo, has made studies of the metabolism and functional responses induced by AGE-modified proteins by RAGE and other putative AGE receptors difficult to understand and interpret. Typical glucose-derived AGE-modified albumin prepared in vitro had approximately 7000 Da mass increment of glycation adducts, approximately 40 to 50 molar equivalents of modification, markedly increased negative charge, bound to RAGE and had rapid clearance by scavenger receptor–mediated removal from circulation in the liver.41Thornalley P.J. Argirova M. Ahmed N. et al.Mass spectrometric monitoring of albumin in uraemia.Kidney Int. 2000; 58: 2228-2234Abstract Full Text Full Text PDF PubMed Google Scholar, 42Westwood M.E. Thornalley P.J. Molecular characteristics of methylglyoxal-modified bovine and human serum albumins. Comparison with glucose-derived advanced glycation endproduct-modified serum albumins.J Prot Chem. 1995; 14: 359-372Crossref PubMed Scopus (167) Google Scholar, 43Matsumoto K. Sano K. Nagai R. et al.Endocytic uptake of advanced glycation end products by mouse liver sinusoidal endothelial cells is mediated by a scavenger receptor distinct from the macrophage scavenger receptor class A.Biochem J. 2000; 352: 233-240Crossref PubMed Scopus (46) Google Scholar In contrast, albumin in vivo typically has <1% modification by one AGE residue, a mass increment of <200 Da (mostly due to early glycation adduct FL), little change in charge, may not always bind RAGE, and shows little extraction from circulation in the liver.13Agalou S. Ahmed N. Babaei-Jadidi R. et al.Profound mishandling of protein glycation degradation products in uremia and dialysis.J Am Soc Nephrol. 2005; 16: 1471-1485Crossref PubMed Scopus (89) Google Scholar, 22Ahmed N. Thornalley P.J. Luthen R. et al.Processing of protein glycation, oxidation and nitrosation adducts in the liver and the effect of cirrhosis.J Hepatol. 2004; 41: 913-919Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar, 41Thornalley P.J. Argirova M. Ahmed N. et al.Mass spectrometric monitoring of albumin in uraemia.Kidney Int. 2000; 58: 2228-2234Abstract Full Text Full Text PDF PubMed Google Scholar, 44Degenhardt T.P. Grass L. Reddy S. et al.The serum concentration of the advanced glycation end-product Nî-(carboxymethyl)lysine is increased in uremia.Kidney Int. 1997; 52: 1064-1067Abstract Full Text PDF PubMed Google Scholar, 45Buetler T.M. Leclerc E. Baumeyer A. et al.N-epsilon-carboxymethyllysine-modified proteins are unable to bind to RAGE and activate an inflammatory response.Mol Nutr Food Res. 2008; 52: 370-378Crossref PubMed Scopus (49) Google Scholar, 46Ng R. Argirov O.K. Ahmed N. et al.Human serum albumin minimally modified by methylglyoxal binds to human mononuclear leukocytes via the RAGE receptor and is displaced by N-carboxymethyl-lysine and hydroimidazolone AGE epitopes.Int Congr Ser. 2002; 1245: 77-81Crossref Google Scholar Mathemat" @default.
• W2788736028 created "2018-03-06" @default.
• W2788736028 creator A5021086938 @default.
• W2788736028 creator A5056708838 @default.
• W2788736028 date "2018-04-01" @default.
• W2788736028 modified "2023-10-14" @default.
• W2788736028 title "Advanced glycation end products in the pathogenesis of chronic kidney disease" @default.
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