Advanced Glycation End Products (AGEs) and Cardiorenal Disorders


Austin J Clin Cardiolog. 2014;1(1): 1008.

Advanced Glycation End Products (AGEs) and Cardiorenal Disorders

Sho-ichi Yamagishi*

Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Japan

*Corresponding author: : Sho-ichi Yamagishi, Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan

Received: January 22, 2014; Accepted: January 25, 2014; Published: January 27, 2014

A non–enzymatic reaction between ketones or aldehydes and the amino groups of proteins, lipids and nucleic acids contributes to the aging of macromolecules [1,2]. This process begins with the conversion of reversible Schiff base adducts, and then to more stable, covalently–bound Amadori rearrangement products [1,2]. Over a course of days to weeks, these early glycation products undergo further reactions and rearrangements to become irreversibly crossedlinked, fluorescent protein derivatives termed advanced glycation end products (AGEs) [1,2]. Under hyperglycemic or oxidative stress conditions such as diabetes, formation and accumulation of AGEs have been known to progress at an accelerated rate [1,2]. There is a rowing body of evidence that AGEs play a role in the pathogenesis of chronic kidney disease (CKD) and cardiovascular disease (CVD) [3–7]. In this short communication, I briefly review the pathological role of AGEs in cardiorenal disorders and its therapeutic intervention by DNA aptamer.

AGEs and CVD

Arterial stiffness is associated with the prevalence of CVD and could predict future cardiovascular events in healthy subjects or patients with CVD [8]. Quantitative and qualitative alterations of collagen and elastin fibers by AGE modification contribute to decreased elastic properties of the vessels, thereby being involved in arterial stiffness [9].

Engagement of receptor for AGEs (RAGE) with the ligand, AGEs elicits oxidative stress generation via NADPH oxidase and subsequently activates the redox–sensitive transcription factor NF–kB, which could promote inflammatory, proliferative, and thrombogenic reactions in vessels, contributing to accelerated atherosclerosis [3–6].

Bone marrow–derived circulating endothelial progenitor cells (EPCs) are critical to vascular repair [10]. Diabetes is associated with endothelial dysfunction, decreased EPC function and mobilization, which could accelerate atherosclerosis and increase the risk for CVD in diabetic patients [10]. The AGE–RAGE interaction has impaired vascular repair not only by inducing apoptotic cell death of EPCs, but also by inhibiting the EPC adhesion, spreading and migration [9]. Serum levels of AGEs are inversely associated with the number and migratory activity of circulating EPCs in apparently healthy subjects, further supporting the clinical relevance of AGEs in impaired endothelial cell repair [11].

Vascular calcification is a common problem among the elderly and the patients with diabetes and CKD, and might be associated with increased morbidity and mortality of CVD [12,13]. We have previously shown that AGEs or RAGE activation induces osteoblastic differentiation of microvascular pericytes or aortic smooth muscle cells, respectively, which would play a role in atherosclerotic plaque calcification in diabetes and CKD.

HDL and its major protein constituent, apolipoprotein AI, promote reverse cholesterol transport, thereby preventing foam cell formation in atherosclerotic lesions by stimulating cholesterol efflux from macrophages [14]. AGEs have been shown to decrease mRNA levels of adenosine triphosphate–binding membrane cassette transporter A1 (ABCA1) and ABCG1 in THP–1 cells, crucial factors in macrophagecholesterol efflux and reverse cholesterol transport, thus implicated in accelerated atherosclerosis in diabetes [14]. Further, we have recently found that AGE–RAGE interaction significantly reduces gene expression of silent mating type information regulator 2 homolog 1 (SIRT1) in THP–1 macrophages, a highly conserved NAD+–dependent protein deacetylase, which could play a protective role against CVD [15]. Given that monocytic SIRT1 expression is decreased in patients with stable coronary artery disease and acute coronary syndromes compared with healthy subjects [16], the pathological crosstalk between AGEs and anti–aging molecules, SIRT could contribute to the development and progression of atherosclerotic CVD as well.

AGEs and CKD

Diabetic nephropathy is a leading cause of end–stage renal disease, and accounts for disabilities and the high mortality rates in patients with diabetes [7]. Diabetic nephropathy is characterized by functional and structural changes in the glomerulus, such as glomerularhyperfiltration, thickening of glomerular basement membranes and an expansion of extracellular matrix in mesangial areas [7]. It ultimately progresses to glomerular sclerosis, which is associated with increased albumin excretion and renal dysfunction.

Interaction of AGEs with RAGE has evoked inflammatory reactions, thereby causing progressive alteration in renal architecture and loss of renal function in diabetes [17–19]. RAGE–overexpressing diabetic mice have shown progressive glomerulosclerosis with renal dysfunction, compared with diabetic littermates lacking the RAGE transgene [17]. Diabetic homozygous RAGE null mice failed to develop significantly increased mesangial matrix expansion or thickening of the glomerular basement membrane [18]. Moreover, deletion of RAGE prevented diabetic nephropathy in the OVE26 type 1 mouse, a model of progressive glomerulosclerosis and decline of renal function [19].

DNA aptamer directed against AGEs (AGE–aptamer)

Aptamers are short, single–stranded DNA or RNA molecules that can bind with high affinity and specificity to a wide range of target proteins [20]. Numerous aptamers have been developed and used in the clinical fields as a tool for modulating the function of various proteins [21].

We have found that high–affinity AGE–aptamer inhibits glomerular hypertrophy and extracellular matrix protein accumulation, decreases urinary excretion levels of albumin, and prevents renal dysfunction in type 2 diabetic animals [22]. In this study, AGE–aptamer directly bound to AGEs and resultantly blocked the binding of AGEs to RAGE, and continuous infusion of AGEs–aptamer dramatically decreased AGE levels in the glomeruli of diabetic mice [22]. So, it is conceivable that AGE–aptamer might decrease the glomerular accumulation of AGEs via the blockade of RAGE–induced, oxidative stress–mediated AGE formation in the kidney. In addition, since turnover rate of aptamerbound AGEs by THP–1 macrophages was increased, AGE–aptamer could enhance the elimination of AGEs from the body through the increased turnover by macrophages.

We have very recently found that AGE–aptamer not only inhibits neointima formation after balloon angioplasty, but also reduces the expression levels of AGEs, RAGE and an oxidative stress marker, 8–hydroxy–2’–deoxyguanosine in balloon–injured arteries [23]. Further, compared with control–aptamer, AGE–aptamer significantly suppressed smooth muscle cell proliferation, macrophage infiltration, and platelet–derived growth factor–BB (PDGF–BB) expression in balloon–injured carotid arteries [23]. These findings suggests that AGE–aptamer might prevent balloon injury–induced neointimal hyperplasia by reducing PDGF–BB and macrophage infiltration via suppression of the AGE–RAGE–mediated oxidative stress generation. Taken together, the observations suggest that blockade of the AGERAGE axis by AGE–aptamer might be a novel therapeutic target for preventing CVD and CKD in diabetes.


This study was supported in part by Grants–in–Aid for Scientific Research (B) from the Ministry of Education, Culture, Sports, Science and Technology, Japan, and by MEXT–Supported Program for the Strategic Research Foundation at Private Universities, the Ministry of Education, Culture, Sports, Science and Technology (MEXT).


  1. Vlassara H, Bucala R. Recent progress in advanced glycation and diabetic vascular disease: role of advanced glycation end paroduct receptors. Diabetes. 1996; 45 Suppl 3: S65-66.
  2. Rahbar S. Novel inhibitors of glycation and AGE formation. Cell Biochem Biophys. 2007; 48: 147-157.
  3. Yamagishi S, Imaizumi T. Diabetic vascular complications: pathophysiology, biochemical basis and potential therapeutic strategy. Curr Pharm Des. 2005; 11: 2279-2299.
  4. Bierhaus A, Hofmann MA, Ziegler R, Nawroth PP. AGEs and their interaction with AGE-receptors in vascular disease and diabetes mellitus. I. The AGE concept. Cardiovasc Res. 1998; 37: 586-600.
  5. Schmidt AM, Stern D. Atherosclerosis and diabetes: the RAGE connection. Curr Atheroscler Rep. 2000; 2: 430-436.
  6. Yamagishi S. Role of advanced glycation end products (AGEs) and receptor for AGEs (RAGE) in vascular damage in diabetes. Exp Gerontol. 2011; 46: 217-224.
  7. Yamagishi S, Fukami K, Ueda S, Okuda S. Molecular mechanisms of diabetic nephropathy and its therapeutic intervention. Curr Drug Targets. 2007; 8: 952-959.
  8. Duprez DA, Cohn JN. Arterial stiffness as a risk factor for coronary atherosclerosis. Curr Atheroscler Rep. 2007; 9: 139-144.
  9. Yamagishi S. Potential clinical utility of advanced glycation end product cross- link breakers in age- and diabetes-associated disorders. Rejuvenation Res. 2012; 15: 564-572.
  10. Hoenig MR, Bianchi C, Rosenzweig A, Sellke FW. Decreased vascular repair and neovascularization with ageing: mechanisms and clinical relevance with an emphasis on hypoxia-inducible factor-1. Curr Mol Med. 2008; 8: 754-767.
  11. Ueda S, Yamagishi S, Matsui T, Noda Y, Ueda S, Jinnouchi Y, Sasaki K, et al. Serum levels of advanced glycation end products (AGEs) are inversely associated with the number and migratory activity of circulating endothelial progenitor cells in apparently healthy subjects. Cardiovasc Ther. 2012; 30: 249-254.
  12. Yamagishi S, Fujimori H, Yonekura H, Tanaka N, Yamamoto H. Advanced glycation endproducts accelerate calciication in microvascular pericytes. Biochem Biophys Res Commun. 1999; 258: 353-357.
  13. Suga T, Iso T, Shimizu T, Tanaka T, Yamagishi S, Takeuchi M, et al. Activation of receptor for advanced glycation end products induces osteogenic differentiation of vascular smooth muscle cells. J Atheroscler Thromb. 2011; 18: 670-683.
  14. Ishibashi Y, Matsui T, Takeuchi M, Yamagishi S. Rosuvastatin blocks advanced glycation end products-elicited reduction of macrophage cholesterol eflux by suppressing NADPH oxidase activity via inhibition of geranylgeranylation of Rac-1. Horm Metab Res. 2011; 43: 619-624.
  15. Ishibashi Y, Nakashima S, Matsui T, Yamagishi S. Rosuvastatin restores advanced glycation end product-induced decrease in sirtuin 1 (SIRT1) mRNA levels in THP-1 monocytic cells through its anti-oxidative properties. Int J Cardiol. 2013; 169: e102-103.
  16. Breitenstein A, Wyss CA, Spescha RD, Franzeck FC, Hof D, Riwanto M, et al. Peripheral blood monocyte Sirt1 expression is reduced in patients with coronary artery disease. PLoS One. 2013; 8: e53106.
  17. Yamamoto Y, Kato I, Doi T, Yonekura H, Ohashi S, Takeuchi M, et al. Development and prevention of advanced diabetic nephropathy in RAGE- overexpressing mice. J Clin Invest. 2001; 108: 261-268.
  18. Wendt TM, Tanji N, Guo J, Kislinger TR, Qu W, Lu Y, et al. RAGE drives the development of glomerulosclerosis and implicates podocyte activation in the pathogenesis of diabetic nephropathy. Am J Pathol. 2003; 162: 1123-1137.
  19. Reiniger N, Lau K, McCalla D, Eby B, Cheng B, Lu Y, et al. Deletion of the receptor for advanced glycation end products reduces glomerulosclerosis and preserves renal function in the diabetic OVE26 mouse. Diabetes. 2010; 59: 2043-2054.
  20. Bock LC, Grifin LC, Latham JA, Vermaas EH, Toole JJ. Selection of single- stranded DNA molecules that bind and inhibit human thrombin. Nature. 1992; 355: 564-566.
  21. Gragoudas ES, Adamis AP, Cunningham ET Jr, Feinsod M, Guyer DR; VEGF Inhibition Study in Ocular Neovascularization Clinical Trial Group. Pegaptanib for neovascular age-related macular degeneration. N Engl J Med. 2004; 351: 2805-2816.
  22. Kaida Y, Fukami K, Matsui T, Higashimoto Y, Nishino Y, Obara N, et al. DNA aptamer raised against AGEs blocks the progression of experimental diabetic nephropathy. Diabetes. 2013; 62: 3241-3250.
  23. Ojima A1, Oda E2, Higashimoto Y2, Matsui T1, Yamagishi SI3. DNA aptamer raised against advanced glycation end products inhibits neointimal hyperplasia in balloon-injured rat carotid arteries. Int J Cardiol. 2014; .

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Citation: Yamagishi S. Advanced Glycation End Products (AGEs) and Cardiorenal Disorders. Austin J Clin Cardiolog. 2014;1(1): 1008. ISSN 2381-9111

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