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Systemic inflammation and oxidative stress in hemodialysis patients are associated with down-regulation of Nrf2

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Abstract

Background

Oxidative stress and inflammation are common features and the main mediators of progression of chronic kidney disease (CKD) and its cardiovascular complications. Under normal conditions, oxidative stress activates the transcription factor, nuclear factor E2-related factor 2 (Nrf2), which is the master regulator of genes encoding antioxidant and detoxifying enzymes and related proteins. The available data on expression of Nrf2 and its key target gene products in CKD patients is limited. We therefore investigated this topic in a group of CKD patients on hemodialysis.

Methods

Twenty adult hemodialysis (HD) patients (aged 54.9 ± 15.2 years) and 11 healthy individuals (aged 50.9 ± 8.0 years) were enrolled. Peripheral blood mononuclear cells (PBMC) were isolated and processed for expression of nuclear factor-κB (NF-κB), Nrf2, heme oxygenase-1 and NADPH: quinoneoxidoreductase 1 (NQO1) by quantitative real-time polymerase chain reaction and western blot analysis. Plasma malondialdehyde (MDA) and tumor necrosis factor-alpha (TNF-α) levels were measured.

Results

Peripheral blood mononuclear cells from HD patients had significantly lower NQO1 and Nrf2 mRNA expressions (0.58 ± 0.35 vs. 1.13 ± 0.64, p = 0.005), and significantly higher NF-κB expression (2.18 ± 0.8 vs. 1.04 ± 0.22, p = 0.0001) compared to the healthy individuals. The NF-κB expression was inversely correlated with Nrf2 levels (r = −0.54, p < 0.01) in CKD patients. Plasma MDA and TNF-α levels were significantly higher in CKD patients than in the healthy individuals.

Conclusions

Up-regulation of NFκB in the CKD patients’ PBMC is coupled to down-regulation of Nrf2 and NQO1 expression. These observations are consistent with recent findings in CKD animals and point to the contribution of the impaired Nrf2 system in the pathogenesis of oxidative stress and inflammation in hemodialysis patients.

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References

  1. Pedruzzi LM, Stockler-Pinto MB, Leite M Jr, Mafra D (2012) Nrf2-keap1 system versus NF-kappaB: the good and the evil in chronic kidney disease? Biochimie 94(12):2461–2466. doi:10.1016/j.biochi.2012.07.015

    Article  CAS  PubMed  Google Scholar 

  2. Small DM, Coombes JS, Bennett N, Johnson DW, Gobe GC (2012) Oxidative stress, anti-oxidant therapies and chronic kidney disease. Nephrology (Carlton) 17(4):311–321. doi:10.1111/j.1440-1797.2012.01572.x

    Article  CAS  Google Scholar 

  3. Bargnoux AS, Cristol JP, Jaussent I, Chalabi L, Bories P, Dion JJ, Henri P, Delage M, Dupuy AM, Badiou S, Canaud B, Morena M (2013) Vitamin E-coated polysulfone membrane improved red blood cell antioxidant status in hemodialysis patients. J Nephrol 26(3):556–563. doi:10.5301/jn.5000195

    Article  CAS  PubMed  Google Scholar 

  4. Zhang W, He J, Zhang F, Huang C, Wu Y, Han Y, Zhao Y (2013) Prognostic role of C-reactive protein and interleukin-6 in dialysis patients: a systematic review and meta-analysis. J Nephrol 26(2):243–253. doi:10.5301/jn.5000169

    Article  PubMed  Google Scholar 

  5. Antunes F, Han D (2009) Redox regulation of NF-kappaB: from basic to clinical research. Antioxid Redox Signal 11(9):2055–2056. doi:10.1089/ARS.2009.2659

    Article  CAS  PubMed  Google Scholar 

  6. Kim J, Cha YN, Surh YJ (2010) A protective role of nuclear factor-erythroid 2-related factor-2 (Nrf2) in inflammatory disorders. Mutat Res 690(1–2):12–23. doi:10.1016/j.mrfmmm.2009.09.007

    Article  CAS  PubMed  Google Scholar 

  7. Rangan G, Wang Y, Harris D (2009) NF-kappaB signalling in chronic kidney disease. Front Biosci J Virtual Libr 14:3496–3522

    Article  CAS  Google Scholar 

  8. Saito H (2013) Toxico-pharmacological perspective of the Nrf2-Keap1 defense system against oxidative stress in kidney diseases. Biochem Pharmacol 85(7):865–872. doi:10.1016/j.bcp.2013.01.006

    Article  CAS  PubMed  Google Scholar 

  9. Ruiz S, Pergola PE, Zager RA, Vaziri ND (2013) Targeting the transcription factor Nrf2 to ameliorate oxidative stress and inflammation in chronic kidney disease. Kidney Int 83(6):1029–1041. doi:10.1038/ki.2012.439

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Slocum SL, Kensler TW (2011) Nrf2: control of sensitivity to carcinogens. Arch Toxicol 85(4):273–284. doi:10.1007/s00204-011-0675-4

    Article  CAS  PubMed  Google Scholar 

  11. Takaya K, Suzuki T, Motohashi H, Onodera K, Satomi S, Kensler TW, Yamamoto M (2012) Validation of the multiple sensor mechanism of the Keap1-Nrf2 system. Free Radic Biol Med 53(4):817–827. doi:10.1016/j.freeradbiomed.2012.06.023

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Singh S, Vrishni S, Singh BK, Rahman I, Kakkar P (2010) Nrf2-ARE stress response mechanism: a control point in oxidative stress-mediated dysfunctions and chronic inflammatory diseases. Free Radical Res 44(11):1267–1288. doi:10.3109/10715762.2010.507670

    Article  CAS  Google Scholar 

  13. Baird L, Dinkova-Kostova AT (2011) The cytoprotective role of the Keap1-Nrf2 pathway. Arch Toxicol 85(4):241–272. doi:10.1007/s00204-011-0674-5

    Article  CAS  PubMed  Google Scholar 

  14. Kim HJ, Vaziri ND (2010) Contribution of impaired Nrf2-Keap1 pathway to oxidative stress and inflammation in chronic renal failure. Am J Physiol Renal Physiol 298(3):662–671. doi:10.1152/ajprenal.00421.2009

    Article  Google Scholar 

  15. Kim HJ, Sato T, Rodriguez-Iturbe B, Vaziri ND (2011) Role of intrarenal angiotensin system activation, oxidative stress, inflammation, and impaired nuclear factor-erythroid-2-related factor 2 activity in the progression of focal glomerulosclerosis. J Pharmacol Exp Ther 337(3):583–590. doi:10.1124/jpet.110.175828

    Article  CAS  PubMed  Google Scholar 

  16. Aminzadeh MA, Nicholas SB, Norris KC, Vaziri ND (2013) Role of impaired Nrf2 activation in the pathogenesis of oxidative stress and inflammation in chronic tubulo-interstitial nephropathy. Nephrol Dial Transplant Off Publ Eur Dial Transpl Assoc Eur Renal Assoc 28(8):2038–2045. doi:10.1093/ndt/gft022

    CAS  Google Scholar 

  17. Daugirdas JT (1993) Second generation logarithmic estimates of single-pool variable volume Kt/V: an analysis of error. J Am Soc Nephrol JASN 4(5):1205–1213

    CAS  PubMed  Google Scholar 

  18. World Health Organization(2000). Obesity: preventing and managing the global epidemic. Report of a WHO consultation. World Health Organization technical report series 894:i–xii, 1–253

  19. Shimazu T, Hirschey MD, Newman J, He W, Shirakawa K, Le Moan N, Grueter CA, Lim H, Saunders LR, Stevens RD, Newgard CB, Farese RV Jr, de Cabo R, Ulrich S, Akassoglou K, Verdin E (2013) Suppression of oxidative stress by beta-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science 339(6116):211–214. doi:10.1126/science.1227166

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Jung KA, Kwak MK (2010) The Nrf2 system as a potential target for the development of indirect antioxidants. Molecules 15(10):7266–7291. doi:10.3390/molecules15107266

    Article  CAS  PubMed  Google Scholar 

  21. Janssen-Heininger YM, Poynter ME, Baeuerle PA (2000) Recent advances towards understanding redox mechanisms in the activation of nuclear factor kappaB. Free Radic Biol Med 28(9):1317–1327

    Article  CAS  PubMed  Google Scholar 

  22. Sun B, Zou X, Chen Y, Zhang P, Shi G (2008) Preconditioning of carbon monoxide releasing molecule-derived CO attenuates LPS-induced activation of HUVEC. Int J Biol Sci 4(5):270–278

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Lin CC, Liu XM, Peyton K, Wang H, Yang WC, Lin SJ, Durante W (2008) Far infrared therapy inhibits vascular endothelial inflammation via the induction of heme oxygenase-1. Arterioscler Thromb Vasc Biol 28(4):739–745. doi:10.1161/ATVBAHA.107.160085

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Jiang T, Huang Z, Lin Y, Zhang Z, Fang D, Zhang DD (2010) The protective role of Nrf2 in streptozotocin-induced diabetic nephropathy. Diabetes 59(4):850–860. doi:10.2337/db09-1342

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Yoh K, Itoh K, Enomoto A, Hirayama A, Yamaguchi N, Kobayashi M, Morito N, Koyama A, Yamamoto M, Takahashi S (2001) Nrf2-deficient female mice develop lupus-like autoimmune nephritis. Kidney Int 60(4):1343–1353. doi:10.1046/j.1523-1755.2001.00939.x

    Article  CAS  PubMed  Google Scholar 

  26. Liu M, Grigoryev DN, Crow MT, Haas M, Yamamoto M, Reddy SP, Rabb H (2009) Transcription factor Nrf2 is protective during ischemic and nephrotoxic acute kidney injury in mice. Kidney Int 76(3):277–285. doi:10.1038/ki.2009.157

    Article  CAS  PubMed  Google Scholar 

  27. Aminzadeh MA, Reisman SA, Vaziri ND, Shelkovnikov S, Farzaneh SH, Khazaeli M, Meyer CJ (2013) The synthetic triterpenoid RTA dh404 (CDDO-dhTFEA) restores endothelial function impaired by reduced Nrf2 activity in chronic kidney disease. Redox Biol 1(1):527–531. doi:10.1016/j.redox.2013.10.007

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Aminzadeh MA, Reisman SA, Vaziri ND, Khazaeli M, Yuan J, Meyer CJ (2013) The synthetic triterpenoid RTA dh404 (CDDO-dhTFEA) restores Nrf2 activity and attenuates oxidative stress, inflammation, and fibrosis in rats with chronic kidney disease. Xenobiotica Fate Foreign Compd Biol Syst. doi:10.3109/00498254.2013.852705

    Google Scholar 

  29. Zheng H, Whitman SA, Wu W, Wondrak GT, Wong PK, Fang D, Zhang DD (2011) Therapeutic potential of Nrf2 activators in streptozotocin-induced diabetic nephropathy. Diabetes 60(11):3055–3066. doi:10.2337/db11-0807

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Tsai PY, Ka SM, Chang JM, Chen HC, Shui HA, Li CY, Hua KF, Chang WL, Huang JJ, Yang SS, Chen A (2011) Epigallocatechin-3-gallate prevents lupus nephritis development in mice via enhancing the Nrf2 antioxidant pathway and inhibiting NLRP3 inflammasome activation. Free Radic Biol Med 51(3):744–754. doi:10.1016/j.freeradbiomed.2011.05.016

    Article  CAS  PubMed  Google Scholar 

  31. Peng A, Ye T, Rakheja D, Tu Y, Wang T, Du Y, Zhou JK, Vaziri ND, Hu Z, Mohan C, Zhou XJ (2011) The green tea polyphenol (-)-epigallocatechin-3-gallate ameliorates experimental immune-mediated glomerulonephritis. Kidney Int 80(6):601–611. doi:10.1038/ki.2011.121

    Article  CAS  PubMed  Google Scholar 

  32. Sahin K, Tuzcu M, Gencoglu H, Dogukan A, Timurkan M, Sahin N, Aslan A, Kucuk O (2010) Epigallocatechin-3-gallate activates Nrf2/HO-1 signaling pathway in cisplatin-induced nephrotoxicity in rats. Life Sci 87(7–8):240–245. doi:10.1016/j.lfs.2010.06.014

    Article  CAS  PubMed  Google Scholar 

  33. Molina-Jijon E, Tapia E, Zazueta C, El Hafidi M, Zatarain-Barron ZL, Hernandez-Pando R, Medina-Campos ON, Zarco-Marquez G, Torres I, Pedraza-Chaverri J (2011) Curcumin prevents Cr(VI)-induced renal oxidant damage by a mitochondrial pathway. Free Radic Biol Med 51(8):1543–1557. doi:10.1016/j.freeradbiomed.2011.07.018

    Article  CAS  PubMed  Google Scholar 

  34. Faraonio R, Vergara P, Di Marzo D, Pierantoni MG, Napolitano M, Russo T, Cimino F (2006) p53 suppresses the Nrf2-dependent transcription of antioxidant response genes. J Biol Chem 281(52):39776–39784. doi:10.1074/jbc.M605707200

    Article  CAS  PubMed  Google Scholar 

  35. Yu M, Li H, Liu Q, Liu F, Tang L, Li C, Yuan Y, Zhan Y, Xu W, Li W, Chen H, Ge C, Wang J, Yang X (2011) Nuclear factor p65 interacts with Keap1 to repress the Nrf2-ARE pathway. Cell Signal 23(5):883–892. doi:10.1016/j.cellsig.2011.01.014

    Article  CAS  PubMed  Google Scholar 

  36. Rieber N, Hector A, Kuijpers T, Roos D, Hartl D (2012) Current concepts of hyperinflammation in chronic granulomatous disease. Clinical Dev Immunol 2012:252460. doi:10.1155/2012/252460

    Article  Google Scholar 

  37. Dworski R, Han W, Blackwell TS, Hoskins A, Freeman ML (2011) Vitamin E prevents NRF2 suppression by allergens in asthmatic alveolar macrophages in vivo. Free Radic Biol Med 51(2):516–521. doi:10.1016/j.freeradbiomed.2011.04.040

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Bolati D, Shimizu H, Yisireyili M, Nishijima F, Niwa T (2013) Indoxyl sulfate, a uremic toxin, downregulates renal expression of Nrf2 through activation of NF-kappaB. BMC Nephrol 14:56. doi:10.1186/1471-2369-14-56

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Zaza G, Granata S, Masola V, Rugiu C, Fantin F, Gesualdo L, Schena FP, Lupo A (2013) Downregulation of nuclear-encoded genes of oxidative metabolism in dialyzed chronic kidney disease patients. PLoS One 8(10):e77847. doi:10.1371/journal.pone.0077847

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Cardozo LF, Pedruzzi LM, Stenvinkel P, Stockler-Pinto MB, Daleprane JB, Leite M Jr, Mafra D (2013) Nutritional strategies to modulate inflammation and oxidative stress pathways via activation of the master antioxidant switch Nrf2. Biochimie 95(8):1525–1533. doi:10.1016/j.biochi.2013.04.012

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We wish to thank the Clínica Nefrológica, Niterói-Rio de Janeiro, for allowing their patients to participate in this study. We also thank Conselho Nacional de Pesquisa (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), and Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ), for the funding.

Conflict of interest

The authors declare there are no conflicts of interest.

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Authors and Affiliations

  1. Graduate Program in Cardiovascular Sciences, Universidade Federal Fluminense (UFF), Niterói, RJ, Brazil

    Liliana M. Pedruzzi, Ludmila F. M. F. Cardozo, Milena B. Stockler-Pinto & Denise Mafra

  2. Department of Basic and Experimental Nutrition, Institute of Nutrition, Universidade Estadual do Rio de Janeiro (UERJ), Rio De Janeiro, Brazil

    Julio B. Daleprane & Elisa B. Monteiro

  3. Division of Nephrology, Universidade Federal do Rio de Janeiro (UFRJ), Rio De Janeiro, Brazil

    Maurilo Leite Jr

  4. Division of Nephrology and Hypertension, University of California, Irvine, CA, USA

    Nosratola D. Vaziri

  5. Rua Lídio Machado, n. 559 ap 401. Santo Andrezinho, Castelo, ES, 29360-000, Brazil

    Liliana M. Pedruzzi

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  1. Liliana M. Pedruzzi
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  2. Ludmila F. M. F. Cardozo
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Correspondence to Liliana M. Pedruzzi.

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Pedruzzi, L.M., Cardozo, L.F.M.F., Daleprane, J.B. et al. Systemic inflammation and oxidative stress in hemodialysis patients are associated with down-regulation of Nrf2. J Nephrol 28, 495–501 (2015). https://doi.org/10.1007/s40620-014-0162-0

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