Horm Metab Res 2015; 47(04): 253-258
DOI: 10.1055/s-0034-1385904
Endocrine Research
© Georg Thieme Verlag KG Stuttgart · New York

DNA Aptamer Raised Against Advanced Glycation End Products (AGEs) Improves Glycemic Control and Decreases Adipocyte Size in Fructose-Fed Rats by Suppressing AGE-RAGE Axis

A. Ojima
1   Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan
,
T. Matsui
1   Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan
,
N. Nakamura
1   Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan
,
Y. Higashimoto
2   Department of Chemistry, Kurume University School of Medicine, Kurume, Japan
,
S. Ueda
3   Department of Medicine, Kurume University School of Medicine, Kurume, Japan
,
K. Fukami
3   Department of Medicine, Kurume University School of Medicine, Kurume, Japan
,
S. Okuda
3   Department of Medicine, Kurume University School of Medicine, Kurume, Japan
,
S. Yamagishi
1   Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan
› Author Affiliations
Further Information

Publication History

received 28 April 2014

accepted 10 July 2014

Publication Date:
08 August 2014 (online)

Abstract

Advanced glycation end products (AGEs) decrease adiponectin expression and suppress insulin signaling in cultured adipocytes through the interaction with a receptor for AGEs (RAGE) via oxidative stress generation. We have recently found that high-affinity DNA aptamer directed against AGE (AGE-aptamer) prevents the progression of experimental diabetic nephropathy by blocking the harmful actions of AGEs in the kidney. This study examined the effects of AGE-aptamer on adipocyte remodeling, AGE-RAGE-oxidative stress axis, and adiponectin expression in fructose-fed rats. Although AGE-aptamer treatment by an osmotic mini pump for 8 weeks did not affect serum insulin levels, it significantly decreased average fasting blood glucose and had a tendency to inhibit body weight gain in fructose-fed rats. Furthermore, AGE-aptamer significantly suppressed the increase in adipocyte size and prevented the elevation in AGEs, RAGE, and an oxidative stress marker, 8-hydroxydeoxyguanosine (8-OHdG), levels in adipose tissues of fructose-fed rats at 14-week-old, while it restored the decrease in adiponectin mRNA levels. Our present study suggests that AGE-aptamer could improve glycemic control and prevent adipocyte remodeling in fructose-fed rats partly by suppressing the AGE-RAGE-mediated oxidative stress generation. AGE-aptamer might be a novel therapeutic strategy for fructose-induced metabolic derangements.

 
  • References

  • 1 Rahbar S. Novel inhibitors of glycation and AGE formation. Cell Biochem Biophys 2007; 48: 147-157
  • 2 Stitt AW, Bucala R, Vlassara H. Atherogenesis and advanced glycation: promotion, progression, and prevention. Ann NY Acad Sci 1997; 811: 115-127
  • 3 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
  • 4 D’Agati V, Yan SF, Ramasamy R, Schmidt AM. RAGE, glomerulosclerosis and proteinuria: roles in podocytes and endothelial cells. Trends Endocrinol Metab 2010; 21: 50-56
  • 5 Yamagishi S, Imaizumi T. Diabetic vascular complications: pathophysiology, biochemical basis and potential therapeutic strategy. Curr Pharm Des 2005; 11: 2279-2299
  • 6 Ward MS, Fortheringham AK, Cooper ME, Forbes JM. Targeting advanced glycation endproducts and mitochondrial dysfunction in cardiovascular disease. Curr Opin Pharmacol 2013; 13: 654-661
  • 7 Gaens KH, Goossens GH, Niessen PM, van Greevenbroek MM, van der Kallen CJ, Niessen HW, Rensen SS, Buurman WA, Greve JW, Blaak EE, van Zandvoort MA, Bierhaus A, Stehouwer CD, Schalkwijk CG. N-{Varepsilon}-(carboxymethyl)lysine-receptor for advanced glycation end product axis is a key modulator of obesity-induced dysregulation of adipokine expression and insulin resistance. Arterioscler Thromb Vasc Biol 2014; 34: 1199-1208
  • 8 Song F, Hurtado Del Pozo C, Rosario R, Zou YS, Ananthakrishnan R, Xu X, Patel PR, Benoit VM, Yan SF, Li H, Friedman RA, Kim JK, Ramasamy R, Ferrante Jr AW, Schmidt AM. RAGE Regulates the Metabolic and Inflammatory Response to High Fat Feeding in Mice. Diabetes 2014; 63: 1948-1965
  • 9 Yamagishi S. Role of advanced glycation end products (AGEs) in osteoporosis in diabetes. Curr Drug Targets 2011; 12: 2096-20102
  • 10 Takeuchi M, Yamagishi S. Possible involvement of advanced glycation end-products (AGEs) in the pathogenesis of Alzheimer’s disease. Curr Pharm Des 2008; 14: 973-978
  • 11 Abe R, Yamagishi S. AGE-RAGE system and carcinogenesis. Curr Pharm Des 2008; 14: 940-945
  • 12 Unoki H, Yamagishi S. Advanced glycation end products and insulin resistance. Curr Pharm Des 2008; 14: 987-989
  • 13 Unoki H, Bujo H, Yamagishi S, Takeuchi M, Imaizumi T, Saito Y. Advanced glycation end products attenuate cellular insulin sensitivity by increasing the generation of intracellular reactive oxygen species in adipocytes. Diabetes Res Clin Pract 2007; 76: 236-244
  • 14 Unoki-Kubota H, Yamagishi S, Takeuchi M, Bujo H, Saito Y. Pyridoxamine, an inhibitor of advanced glycation end product (AGE) formation ameliorates insulin resistance in obese, type 2 diabetic mice. Protein Pept Lett 2010; 17: 1177-1181
  • 15 Tahara N, Yamagishi S, Matsui T, Takeuchi M, Nitta Y, Kodama N, Mizoguchi M, Imaizumi T. Serum levels of advanced glycation end products (AGEs) are independent correlates of insulin resistance in nondiabetic subjects. Cardiovasc Ther 2012; 30: 42-48
  • 16 Ellington AD, Szostak JW. In vitro selection of RNA molecules that bind specific ligands. Nature 1990; 346: 818-822
  • 17 Gragoudas ES, Adamis AP, Cunningham ET, Feinsod M, Guyer DR. Group VISiONCT . Pegaptanib for neovascular age-related macular degeneration. N Engl J Med 2004; 351: 2805-2816
  • 18 Jilma-Stohlawetz P, Gilbert JC, Gorczyca ME, Knöbl P, Jilma B. A dose ranging phase I/II trial of the von Willebrand factor inhibiting aptamer ARC1779 in patients with congenital thrombotic thrombocytopenic purpura. Thromb Haemost 2011; 106: 539-547
  • 19 Kaida Y, Fukami K, Matsui T, Higashimoto Y, Nishino Y, Obara N, Nakayama Y, Ando R, Toyonaga M, Ueda S, Takeuchi M, Inoue H, Okuda S, Yamagishi S. DNA aptamer raised against AGEs blocks the progression of experimental diabetic nephropathy. Diabetes 2013; 62: 3241-3250
  • 20 Ojima A, Oda E, Higashimoto Y, Matsui T, Yamagishi S. DNA aptamer raised against advanced glycation end products inhibits neointimal hyperplasia in balloon-injured rat carotid arteries. Int J Cardiol 2014; 171: 443-446
  • 21 Ojima A, Matsui T, Maeda S, Takeuchi M, Inoue H, Higashimoto Y, Yamagishi S. DNA aptamer raised against advanced glycation end products inhibits melanoma growth in nude mice. Lab Invest 2014; 94: 422-429
  • 22 Hwang IS, Ho H, Hoffman BB, Reaven GM. Fructose-induced insulin resistance and hypertension in rats. Hypertension 1987; 10: 512-516
  • 23 Yamagishi S, Nakamura K, Matsui T, Inagaki Y, Takenaka K, Jinnouchi Y, Yoshida Y, Matsuura T, Narama I, Motomiya Y, Takeuchi M, Inoue H, Yoshimura A, Bucala R, Imaizumi T. Pigment epithelium-derived factor inhibits advanced glycation end product-induced retinal vascular hyperpermeability by blocking reactive oxygen species-mediated vascular endothelial growth factor expression. J Biol Chem 2006; 281: 20213-20220
  • 24 Takeuchi M, Makita Z, Bucala R, Suzuki T, Koike T, Kameda Y. Immunological evidence that non-carboxymethyllysine advanced glycation end-products are produced from short chain sugars and dicarbonyl compounds in vivo. Mol Med 2000; 6: 114-125
  • 25 Tahara N, Yamagishi S, Takeuchi M, Honda A, Tahara A, Nitta Y, Kodama N, Mizoguchi M, Kaida H, Ishibashi M, Hayabuchi N, Matsui T, Imaizumi T. Positive association between serum level of glyceraldehyde-derived advanced glycation end products and vascular inflammation evaluated by [(18)F]fluorodeoxyglucose positron emission tomography. Diabetes Care 2012; 35: 2618-2625
  • 26 Matsui T, Nishino Y, Ojima A, Maeda S, Tahara N, Yamagishi S. Pigment epithelium-derived factor improves metabolic derangements and ameliorates dysregulation of adipocytokines in obese type 2 diabetic rats. Am J Pathol 2014; 184: 1094-1103
  • 27 Johnson RJ, Nakagawa T, Sanchez-Lozada LG, Shafiu M, Sundaram S, Le M, Ishimoto T, Sautin YY, Lanaspa MA. Sugar uric acid, and the etiology of diabetes and obesity. Diabetes 2013; 62: 3307-3315
  • 28 Feinman RD, Fine EJ. Fructose in perspective. Nutr Metab (Lond) 2013; 10: 45
  • 29 Jia X, Wu L. Accumulation of endogenous methylglyoxal impaired insulin signaling in adipose tissue of fructose-fed rats. Mol Cell Biochem 2007; 306: 133-139
  • 30 Soro-Paavonen A, Watson AM, Li J, Paavonen K, Koitka A, Calkin AC, Barit D, Coughlan MT, Drew BG, Lancaster GI, Thomas M, Forbes JM, Nawroth PP, Bierhaus A, Cooper ME, Jandeleit-Dahm KA. Receptor for advanced glycation end products (RAGE) deficiency attenuates the development of atherosclerosis in diabetes. Diabetes 2008; 57: 2461-2469
  • 31 Maeda S, Matsui T, Takeuchi M, Yamagishi S. Co-treatment with azelinidipine and olmesartan inhibits advanced glycation end products (AGEs) elicited down-regulation of adiponectin mRNA levels in cultured adipocytes partly via its anti-oxidative property. Int J Cardiol 2011; 146: 264-266
  • 32 Maeda S, Matsui T, Takeuchi M, Yamagishi S. Pigment epithelium-derived factor (PEDF) blocks advanced glycation end products (AGEs)-RAGE-induced suppression of adiponectin mRNA level in adipocytes by inhibiting NADPH oxidase-mediated oxidative stress generation. Int J Cardiol 2011; 152: 408-410
  • 33 Mangge H, Almer G, Truschnig-Wilders M, Schmidt A, Gasser R, Fuchs D. Inflammation, adiponectin, obesity and cardiovascular risk. Curr Med Chem 2010; 17: 4511-4520
  • 34 Cruciani-Guglielmacci C, Vincent-Lamon M, Rouch C, Orosco M, Ktorza A, Magnan C. Early changes in insulin secretion and action induced by high-fat diet are related to a decreased sympathetic tone. Am J Physiol Endocrinol Metab 2005; 288: E148-E154