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AGE

, Volume 32, Issue 2, pp 197–208 | Cite as

Kaempferol modulates pro-inflammatory NF-κB activation by suppressing advanced glycation endproducts-induced NADPH oxidase

  • Ji Min Kim
  • Eun Kyeong Lee
  • Dae Hyun Kim
  • Byung Pal Yu
  • Hae Young ChungEmail author
Article

Abstract

Advanced glycation endproducts (AGE) are oxidative products formed from the reaction between carbohydrates and a free amino group of proteins that are provoked by reactive species (RS). It is also known that AGE enhance the generation of RS and that the binding of AGE to a specific AGE receptor (RAGE) induces the activation of the redox-sensitive, pro-inflammatory transcription factor, nuclear factor-kappa B (NF-ĸB). In this current study, we investigated the anti-oxidative effects of short-term kaempferol supplementation on the age-related formation of AGE and the binding activity of RAGE in aged rat kidney. We further investigated the suppressive action of kaempferol against AGE's ability to stimulate activation of pro-inflammatory NF-ĸB and its molecular mechanisms. For this study, we utilized young (6 months old), old (24 months old), and kaempferol-fed (2 and 4 mg/kg/day for 10 days) old rats. In addition, for the molecular work, the rat endothelial cell line, YPEN-1 was used. The results show that AGE and RAGE were increased during aging and that these increases were blunted by kaempferol. In addition, dietary kaempferol reduced age-related increases in NF-κB activity and NF-ĸB-dependant pro-inflammatory gene activity. The most significant new finding from this study is that kaempferol supplementation prevented age-related NF-κB activation by suppressing AGE-induced nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase). Taken together, our results demonstrated that dietary kaempferol exerts its anti-oxidative and anti-inflammatory actions by modulating the age-related NF-κB signaling cascade and its pro-inflammatory genes by suppressing AGE-induced NADPH oxidase activation. Based on these data, dietary kaempferol is proposed as a possible anti-AGE agent that may have the potential for use in anti-inflammation therapies.

Keywords

Kaempferol Aging NF-κB AGE NADPH oxidase Anti-inflammation 

Notes

Acknowledgements

This work was supported by National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (20090093226). We thank Aging Tissue Bank for providing research samples.

References

  1. Asgary S, Naderi GA, Zadegan NS, Vakili R (2002) The inhibitory effects of pure flavonoids on in vitro protein glycosylation. J Herb Pharmacother 2:47–55CrossRefPubMedGoogle Scholar
  2. Bierhause A, Hofmann MA, Ziegler R, Nawroth PP (1988) The AGE/RAGE pathway in vascular disease and diabetes mellitus. Part І. The AGE-concept. Cadiovasc. Res. 37:586-600. Biogerontology 4:399–408Google Scholar
  3. Bronska M, Czuba ZP, Krol W (2003) Effect of flavone derivatives on interleukin 1β mRNA expression and IL-1β protein synthesis in stimulated RAW 264.7 macrophages. Scand J Immunol 57:162–166CrossRefGoogle Scholar
  4. Brownlee M (1995a) Advanced protein glycosylation in diabetes and aging. Annu Rev Med 46:223–234CrossRefPubMedGoogle Scholar
  5. Brownlee M (1995b) Biochemistry and molecular cell biology of diabetic complications. Nature 6865:813–820Google Scholar
  6. Bucala R, Cerami A (1992) Advanced glycosylation: chemistry, biology, and implications for diabetes and aging. Adv Pharmacol 23:1–34CrossRefPubMedGoogle Scholar
  7. Cai W, He JC, Zhu L, Peppa M, Lu C, Uribarri J, Vlassara H (2004) High levels of dietary advanced glycation end products transform low-density lipoprotein into a potent redox-sensitive mitogen-activated protein kinase stimulant in diabetic patients. Circulation 3:285–291CrossRefGoogle Scholar
  8. Corsini E, Terzoli A, Bruccoleri A, Marinovich M, Galli CL (1997) Induction of tumor necrosis factor-alpha in vivo by a skin irritant, tributyltin, through activation of transcription factors: its pharmacological modulation by anti-inflammatory drugs. J Invest Dermatol 108(6):892–896CrossRefPubMedGoogle Scholar
  9. Csiszar A, Ungvari Z, Edwards JG, Kaminski P, Wolin MS, Koller A, Kaley G (2002) Aging-induced phenotypic changes and oxidative stress impair coronary arteriolar function. Circ Res 11:1159–1166CrossRefGoogle Scholar
  10. García-Mediavilla V, Crespo I, Collado PS, Esteller A, Sánchez-Campos S, Tuñón MJ, González-Gallego J (2007) The anti-inflammatory flavones quercetin and kaempferol cause inhibition of inducible nitric oxide synthase, cyclooxygenase-2 and reactive C-protein, and down-regulation of the nuclear factor kappaB pathway in Chang Liver cells. Eur J Pharmacol 2- 3:221–229CrossRefGoogle Scholar
  11. Go EK, Jung KJ, Kim JY, Yu BP, Chung HY (2005) Betaine suppresses proinflammatory signaling during aging: the involvement of nuclear factor-kappaB via nuclear factor-inducing kinase/IkappaB kinase and mitogen-activated protein kinases. J Gerontol A Biol Sci Med Sci 60(10):1252–1264PubMedGoogle Scholar
  12. Griendling KK, Sorescu D, Ushio-Fukai M (2000) NAD(P)H oxidase: role in cardiovascular biology and disease. Circ Res 86(5):494–501, ReviewPubMedGoogle Scholar
  13. Hamilton CA, Brosnan MJ, McIntyre M, Graham D, Dominiczak AF (2001) Superoxide excess in hypertension and aging: a common cause of endothelial dysfunction. Hypertension 2 Part 2:529–534Google Scholar
  14. Hatada EN, Krappmann D, Scheidereit C (2000) NF-kappaB and the innate immune response. Curr Opin Immunol 12(1):52–58, ReviewCrossRefPubMedGoogle Scholar
  15. Hofmann MA, Drury S, Fu C, Qu W, Taguch A, Lu Y, Avila C, Kambham N, Bierhaus A, Nawroth P, Neutath MF, Slattery T, Beach D, McClary J, Nagashimura M, Moreser J, Stern D, Schmidt AM (1996) RAGE mediates a novel pro inflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides. Cell 97:889–901CrossRefGoogle Scholar
  16. Huang SM, Wu CH, Yen GC (2006) Effects of flavonoids on the expression of the pro-inflammatory response in human monocytes induced by ligation of the receptor for AGE. Mol Nutr Food Res 12:1129–1139CrossRefGoogle Scholar
  17. Jiang XH, Tu SP, Cui JT, Lin MC, Xia HH, Wong WM, Chan AO, Yuen MF, Jiang SH, Lam SK, Kung HF, Soh JW, Weinstein IB, Wong BC (2004) Antisense targeting protein kinase C alpha and beta1 inhibits gastric carcinogenesis. Cancer Res 16:5787–5794CrossRefGoogle Scholar
  18. Jung HA, Jung YJ, Yoon NY, Jeong da M, Bae HJ, Kim DW, Na DH, Choi JS (2008) Inhibitory effects of Nelumbo nucifera leaves on rat lens aldose reductase, advanced glycation endproducts formation, and oxidative stress. Food Chem Toxicol 12:3818–3826Google Scholar
  19. Jung KJ, Lee EK, Kim JY, Zou Y, Sung B, Heo HS, Kim MK, Lee J, Kim ND, Yu BP, Chung HY (2009) Effect of short term calorie restriction on pro-inflammatory NF-kB and AP-1 in aged rat kidney. Inflamm Res 58(3):143–150CrossRefPubMedGoogle Scholar
  20. Kerr LD (1995) Electrophoretic mobility shift assay. Methods Enzymol 254:619–632CrossRefPubMedGoogle Scholar
  21. Kim HK, Park HR, Lee JS, Chung TS, Chung HY, Chung J (2007) Down-regulation of iNOS and TNF-alpha expression by kaempferol via NF-kappaB inactivation in aged rat gingival tissues. Biogerontology 8(4):399–408CrossRefPubMedGoogle Scholar
  22. Kim JY, Jung KJ, Choi JS, Chung HY (2006) Modulation of the age-related nuclear factor-kappaB (NF kappaB) pathway by hesperetin. Aging Cell 5(5):401–411CrossRefPubMedGoogle Scholar
  23. Kislinger T, Fu C, Huber B, Ou W, Taguchi A, Du Yan S, Hofmann M, Yan SF, Pischetsrieder M, Stern DM, Schmidt AM (1999) 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. J Bio Chem 44:31740–31749CrossRefGoogle Scholar
  24. Labuza TP, Baisier W (1992) The role of the Federal Government in food safety. Crit Rev Food Sci Nutr 31:165–176CrossRefPubMedGoogle Scholar
  25. Lee VS, Dou J, Chen RJ, Lin RS, Lee MR, Tzen JT (2008) Massive accumulation of gallic acid and unique occurrence of myricetin, quercetin, and kaempferol in preparing old oolong tea. J Agric Food Chem 17:7950–7956CrossRefGoogle Scholar
  26. Li J, Schmidt AM (1997) Characterization and functional analysis of the promoter of RAGE, the receptor for advanced glycation end products. J Biol Chem 26:16498–16506CrossRefGoogle Scholar
  27. Li J-M, Shah AM (2001) Differential NADPH- versus NADH-dependent superoxide production by phagocyte-type endothelial cell NADPH oxidase. Cardiovasc Res 52:477–486CrossRefPubMedGoogle Scholar
  28. Liang YX, Wang Z, Li DD, Jiang JM, Shao RG (2003) Effects of aging and advanced glycation on gene expression in cerebrum and spleen of mice. Biomed Environ Sci 16:323–332PubMedGoogle Scholar
  29. Lu C, He JC, Cai W, Liu H, Zhu L, Vlassara H (2004) Advanced glycation endproduct (AGE) receptor 1 is a negative regulator of the inflammatory response to AGE in mesangial cells. Proc Natl Acad Sci USA 32:11767–11772CrossRefGoogle Scholar
  30. Nakayama H, Mitsuhashi T, Kuwajima S, Aoki S, Kuroda Y, Itoh T, Nakagawa S (1993) Immunochemical detection of advanced glycation end products in lens crystallins from streptozocin-induced diabetic rat. Diabetes 42(2):345–350CrossRefPubMedGoogle Scholar
  31. Ramana KV, Friedrich B, Srivastava S, Bhatnagar A, Srivastava SK (2004) Activation of nuclear factor-kappaB by hyperglycemia in vascular smooth muscle cells is regulated by aldose reductase. Diabetes 11:2910–2920CrossRefGoogle Scholar
  32. Ramasamy R, Yan SF, Schmidt AM (2005) The RAGE axis and endothelial dysfunction: maladaptive roles in the diabetic vasculature and beyond. Trends Cardiovasc Med 15(7):237–43CrossRefPubMedGoogle Scholar
  33. Schleicher ED, Wagner E, Nerlich AG (1997) Increased accumulation of the glycoxidation product N(epsilon)-(carboxymethyl)lysine in human tissues in diabetes and aging. J Clin Invest 3:457–468CrossRefGoogle Scholar
  34. Schmidt AM, Yan SD, Wautier JL, Stern D (1999) Activation of receptor for advanced glycation end products: a mechanism for chronic vascular dysfunction in diabetic vasculopathy and atherosclerosis. Cir Res 84:489–497Google Scholar
  35. Shi Y, Vanhoutte PM (2008) Oxidative stress and COX cause hyper-responsiveness in vascular smooth muscle of the femoral artery from diabetic rats. Br J Pharmacol 3:639–651CrossRefGoogle Scholar
  36. Slatter DA, Murray M, Bailey AJ (1998) Formation of a dihydropyridine derivative as a potential cross-link derived from malondialdehyde in physiological systems. FEBS Lett 421(3):180–184CrossRefPubMedGoogle Scholar
  37. Sumi D, Ignarro LJ (2004) Regulation of inducible nitric oxide synthase expression in advanced glycation end product-stimulated raw 264.7 cells: the role of heme oxygenase-1 and endogenous nitric oxide. Diabetes 53(7):1841–1850CrossRefPubMedGoogle Scholar
  38. Thornally PJ (1998) Cell activation by glycated proteins: AGE receptoer recognition factors and functional classification of AGE. Cell Mol Biol 44:1013–1023Google Scholar
  39. Umezawa K, Chaicharoenpong C (2002) Molecular design and biological activities of NF-kappaB inhibitors. Mol Cells 4(2):163–167, ReviewGoogle Scholar
  40. Umezawa K, Ariga A, Matsumoto N (2000) Naturally occurring and synthetic inhibitors of NF-kappaB functions. Anticancer Drug Des 5(4):239–244, ReviewGoogle Scholar
  41. Vlassa H, Bucala R, Striker L (1994) Pathogenic effects of advanced glycosylation: biochemical, biologic, and clinical implications for diabetes and aging. Lab Invest 70:138–151Google Scholar
  42. Wautier J, Guillausseau P (2003) Advanced glycation end products, their receptors and diabetic angiopathy. Diabets Metab 29(1):86–87CrossRefGoogle Scholar
  43. Wautier MP, Chappey O, Corda S, Stern DM, Schmidt AM, Wautier JL (2001) Activation of NADPH oxidase by AGE links oxidant stress to altered gene expression via RAGE. Am J Physiol Endocrinol Metab 280(5):E685–E694PubMedGoogle Scholar
  44. Winlove CP, Parker KH, Avery NC, Bailey AJ (1996) Interactions of elastin and aorta with sugars in vitro and their effects on biochemical and physical properties. Diabetologia 39(10):1131–1139CrossRefPubMedGoogle Scholar
  45. Yamaguchi F, Ariga T, Yoshimura Y, Nakazawa H (2000) Antioxidative and anti-glycation activity of garcinol from Garcinia indica fruit rind. J Agric Food Chem 48(2):180–185CrossRefPubMedGoogle Scholar
  46. Yan SD, Chen X, Fu J, Chen M, Zhu H, Roher A, Slattery T, Zhao J, Magashima M, Morser J, Migheli A, Nawroth P, Stern D, Schmidt AM (1996) RAGE and amyloid beta peptide neurotoxicity in Alzheimer's disease. Nature 382:685–691CrossRefPubMedGoogle Scholar

Copyright information

© American Aging Association, Media, PA, USA 2010

Authors and Affiliations

  • Ji Min Kim
    • 1
  • Eun Kyeong Lee
    • 1
  • Dae Hyun Kim
    • 1
  • Byung Pal Yu
    • 2
    • 3
  • Hae Young Chung
    • 1
    • 2
    Email author
  1. 1.Department of Pharmacy, College of PharmacyPusan National UniversityBusanKorea
  2. 2.Molecular Inflammation Research Center for Aging InterventionPusan National UniversityBusanSouth Korea
  3. 3.Department of PhysiologyThe University of Texas Health Science Center at San AntonioSan AntonioUSA

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