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Differential expressions of antioxidant status in aging rats: the role of transcriptional factor Nrf2 and MAPK signaling pathway

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Abstract

Antioxidant enzymes (AOEs) play an important role in the protection of cells against reactive oxygen species and facilitate the prevention of oxidative stress-induced aging. In the present study, the antioxidant indices, including the content of peroxidation product and the expression of AOEs in rat livers of varying ages (2, 12 and 18–24 months old) were evaluated. Erythrocytes haemolysis induced by free radicals showed significant age-dependent increases (P < 0.05). The content of oxidation products in livers showed that increasing age was associated with serious oxidative injury. The activities of AOEs decreased with increasing age. Expression of the antioxidant and age-related gene, klotho, decreased with increasing age. Western blot assay showed that aged rats experience higher levels of oxidative stress. Nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) exhibited an age-dependent decrease. Additionally, the mitogen-activated protein kinase cascade (MAPK) played a regulatory role in signaling transduction. Overall, we suggest that age-related declines of the antioxidant defense are closely involved with the expression of Nrf2 and are regulated by the MAPK family.

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Abbreviations

AOEs:

Antioxidant enzymes

ARE:

Antioxidant response element

CAT:

Catalase

ERK:

Extracellular responsive kinase

GPx:

Glutathione peroxidase

GR:

Glutathione reductase

JNK:

c-Jun NH2-terminal kinase

MAPK:

Mitogen-activated protein kinase

MDA:

Malondialdehyde

NQO1:

NAD(P)H:quinone oxidoreductase 1

Nrf2:

Nuclear factor-erythroid 2 p45-related factor 2

TBARS:

Thiobarbituric acid reactive substances

References

  • Aebi H (1984) Catalase in vitro. Methods Enzymol 105:121–126

    PubMed  CAS  Google Scholar 

  • Block G, Dietrich M, Norkus EP, Packer L (2003) Oxidative stress in human populations. In: Cutler RG, Rodriguez H (eds) Critical reviews of oxidative stress and aging: advances in basic science diagnostics and intervention. World Scientific Publishing, Singapore, pp 870–880

    Google Scholar 

  • Buege AJ, Aust SD (1978) Microsomal lipid peroxidation. Methods Enzymol 52:302–310

    Article  PubMed  CAS  Google Scholar 

  • Cejkova J, Vejrazka M, Platenik J, Stipek S (2004) Age-related changes in superoxide dismutase, glutathione peroxidase, catalase and xanthine oxidoreductase/xanthine oxidase activities in the rabbit cornea. Exp Gerontol 39:1537–1543

    Article  PubMed  CAS  Google Scholar 

  • Chen C, Pung D, Leong V, Hebbar V, Shen G, Nair S, Li␣W, Kong ANT (2004) Induction of detoxifying enzymes by garlic organosulfur compounds through transcription factor Nrf2: effect of chemical structure and stress signals. Free Radic Biol Med 37:1578– 1590

    Article  PubMed  CAS  Google Scholar 

  • Dent P, Yacoub A, Fisher PB, Hagan MP, Grant S (2003) MAPK pathways in radiation responses. Oncogene 22:5885–5896

    Article  PubMed  CAS  Google Scholar 

  • Devasagayam TP, Tilak JC, Boloor KK, Sane KS, Ghaskadbi SS, Lele RD (2004) Free radicals and antioxidants in human health: current status and future prospects. J Assoc Physicians India 52:794–804

    PubMed  CAS  Google Scholar 

  • Hayes JD, Chanas SA, Henderson CJ, McMahon M, Sun C, Moffat GJ, Wolf CR, Yamamoto M (2000) The Nrf2 transcription factor contributes both to the basal expression of glutathione S-transferases in mouse liver and to their induction by the chemopreventive synthetic antioxidants, butylated hydroxyanisole and ethoxyquin. Biochem Soc Trans 28:33–41

    PubMed  CAS  Google Scholar 

  • Hipkiss AR, Brownson C, Carrier MM (2001) Carnosine, the anti-ageing, anti-oxidant dipeptide, may react with protein carbonyl groups. Mech Ageing Dev 122:1431–1445

    Article  PubMed  CAS  Google Scholar 

  • Ikushima M, Rakugi H, Ishikawa K, Maekawa Y, Yamamoto K, Ohta J, Chihara Y, Kida I, Ogihara T (2006) Anti-apoptotic and anti-senescence effects of Klotho on vascular endothelial cells. Biochem Biophys Res Commun 339:827–832

    Article  PubMed  CAS  Google Scholar 

  • Jaiswal AK, Mcbride OW, Adesnik M, Nebert DW (1988) Human dioxin-inducible cytosolic NADP(H):menadione oxidoreductase. cDNA sequence and localization of gene to chromosome. J Biol Chem 263:13572–13578

    PubMed  CAS  Google Scholar 

  • Johnson GL, Lapadat R (2002) Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science 298:1911–1912

    Article  PubMed  CAS  Google Scholar 

  • Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, Ohyama Y, Kurabayashi M, Kaname T, Kume E, Iwasaki H, Iida A, Shiraki-Iida T, Nishikawa S, Nagai R, Nabeshima YI (2005) Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 390:45–51

    Article  Google Scholar 

  • Kuroso H, Yamamoto M, Clark JD, Pastor JV, Nandi A, Gurnani P, McGuinness OP, Chikuda H, Yamaguchi M, Kawaguchi H, Shimomura I, Takayama Y, Herz J, Kahn CR, Rosenblatt KP, Kuro-o M (2005) Suppression of aging in mice by the hormone Klotho. Science 16:1829–1833

    Article  CAS  Google Scholar 

  • Lee JS, Surh YJ (2005) Nrf2 as a novel molecular target for chemoprevention. Cancer Lett 224:171–184

    Article  PubMed  CAS  Google Scholar 

  • Mohandas J, Marshall JJ, Duggin GG, Horvath JS, Tiller DJ (1984) Low activities of glutathione-related enzymes as factors in the genesis of urinary bladder cancer. Cancer Res 44:5086–5091

    PubMed  CAS  Google Scholar 

  • Nguyen T, Sherratt PJ, Pickett CB (2003) Regulatory mechanisms controlling gene expression mediated by the antioxidant response element. Annu Rev Pharmacol Toxicol 43:233–260

    Article  PubMed  CAS  Google Scholar 

  • Nioi P, Hayes JD (2004) Contribution of NAD(P)H: quinone oxidoreductase 1 to protection against carcinogenesis, and regulation of its gene by the Nrf2 basic-region leucine zipper and the arylhydrocarbon receptor basic helix-loop-helix transcription factors. Mutat Res 555:149–171

    PubMed  CAS  Google Scholar 

  • Rao G, Xia E, Richardson A (1990) Effect of age on the expression of antioxidant enzymes in male Sisher F-344 rats. Mech Ageing Dev 53:49–60

    Article  PubMed  CAS  Google Scholar 

  • Reed DJ, Babson JR, Beatty PW, Brodie AE, Ellis WW, Potter DW (1980) High-performance liquid chromatography analysis of nanomole levels of glutathione, glutathione disulfide, and related thiols and disulfides. Anal Biochem 106:55–62

    Article  PubMed  CAS  Google Scholar 

  • Sanz N, Diez-Fernandez C, Andres D, Cascales M (2002) Hepatotoxicity and aging: endogenous antioxidant systems in hepatocytes from 2-, 6-, 12-, 18- and 30-month-old rats following a necrogenic dose of thioacetamide. Biochim Biophys Acta 1587:12–20

    PubMed  CAS  Google Scholar 

  • Semsei I, Rao G, Richardson A (1989) Changes in the expression of superoxide dismutase and catalase as a function of age and dietary restriction. Biochem Biophys Res Commun 164:620–625

    Article  PubMed  CAS  Google Scholar 

  • Shen G, Hebbar V, Nair S, Xu C, Li W, Lin W (2004) Regulation of Nrf2 transactivation domain activity. The differential effects of mitogen-activated protein kinase cascades and synergistic stimulatory effect of Raf and CREB-binding protein. J Biol Chem 279:23052–23060

    Article  PubMed  CAS  Google Scholar 

  • Suh JH, Shenvi SV, Dixon BM, Liu H, Jaiswal AK, Liu RM, Hagen TM (2004) Decline in transcriptional activity of Nrf2 causes age-related loss of glutathione synthesis, which is reversible with lipoic acid. Proc Natl Acad Sci USA 101:3381–3386

    Article  PubMed  CAS  Google Scholar 

  • Takahashi Y, Kuro-o M, Ishikawa F (2000) Aging mechanisms. Proc Natl Acad Sci USA 97:12407–12408

    Article  PubMed  CAS  Google Scholar 

  • Touyz RM, Schiffrin EL (2004) Reactive oxygen species in vascular biology: implications in hypertension. Histochem Cell Biol 122:339–352

    Article  PubMed  CAS  Google Scholar 

  • Yamamoto M., Clark JD, Pastor JV, Gurnani P, Nandi A, Kurosu H, Miyoshi M, Ogawa Y, Castrillon DH, Rosenblatt KP, Kuro-o M (2005) Regulation of oxidative stress by the anti-aging hormone klotho. J Biol Chem 280:38029–38034

    Article  PubMed  CAS  Google Scholar 

  • Zhu Q, Hackman RM, Ensunsa JL (2002) Antioxidative activities of Oolong tea. J Agric Food Chem 50:6929–6934

    Article  PubMed  CAS  Google Scholar 

  • Zou CG, Agar NS, Jones GL (2001) Oxidative insult to human red blood cells induced by free radical initiator AAPH and its inhibition by a commercial antioxidant mixture. Life Sci 69:75–86

    Article  PubMed  CAS  Google Scholar 

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Acknowledgement

This research was partially supported by the National Science Council (NSC94-2321-B005-005), Taiwan, Republic of China.

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Correspondence to Gow-Chin Yen.

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Shih, PH., Yen, GC. Differential expressions of antioxidant status in aging rats: the role of transcriptional factor Nrf2 and MAPK signaling pathway. Biogerontology 8, 71–80 (2007). https://doi.org/10.1007/s10522-006-9033-y

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  • DOI: https://doi.org/10.1007/s10522-006-9033-y

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