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Oxidative Medicine and Cellular Longevity
Volume 2016, Article ID 7469326, 8 pages
http://dx.doi.org/10.1155/2016/7469326
Review Article

Nrf2 Is an Attractive Therapeutic Target for Retinal Diseases

1Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
2Asubio Pharma Co., Ltd., 6-4-3 Minatojima-Minamimachi, Chuo-ku, Hyogo 650-0047, Japan

Received 20 July 2016; Revised 7 September 2016; Accepted 21 September 2016

Academic Editor: Takeshi Matsugi

Copyright © 2016 Yasuhiro Nakagami. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. D. Harman, “Aging: a theory based on free radical and radiation chemistry,” Journal of Gerontology, vol. 11, no. 3, pp. 298–300, 1956. View at Publisher · View at Google Scholar · View at Scopus
  2. K. L. DeBalsi, K. E. Hoff, and W. C. Copeland, “Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases,” Ageing Research Reviews, 2016. View at Publisher · View at Google Scholar
  3. R. D. Glickman, “Ultraviolet phototoxicity to the retina,” Eye and Contact Lens, vol. 37, no. 4, pp. 196–205, 2011. View at Publisher · View at Google Scholar · View at Scopus
  4. M. Majdi, B. Y. Milani, A. Movahedan, L. Wasielewski, and A. R. Djalilian, “The role of ultraviolet radiation in the ocular system of mammals,” Photonics, vol. 1, no. 4, pp. 347–368, 2014. View at Publisher · View at Google Scholar
  5. J. W. Crabb, M. Miyagi, X. Gu et al., “Drusen proteome analysis: an approach to the etiology of age-related macular degeneration,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 23, pp. 14682–14687, 2002. View at Publisher · View at Google Scholar · View at Scopus
  6. H.-P. Hammes, H. Hoerauf, A. Alt et al., “N(ε)(carboxymethyl)lysin and the AGE receptor RAGE colocalize in age-related macular degeneration,” Investigative Ophthalmology & Visual Science, vol. 40, no. 8, pp. 1855–1859, 1999. View at Google Scholar · View at Scopus
  7. S. R. Kim, S. Jockusch, Y. Itagaki, N. J. Turro, and J. R. Sparrow, “Mechanisms involved in A2E oxidation,” Experimental Eye Research, vol. 86, no. 6, pp. 975–982, 2008. View at Publisher · View at Google Scholar · View at Scopus
  8. J. R. Sparrow, H. R. Vollmer-Snarr, J. Zhou et al., “A2E-epoxides damage DNA in retinal pigment epithelial cells. Vitamin E and other antioxidants inhibit A2E-epoxide formation,” The Journal of Biological Chemistry, vol. 278, no. 20, pp. 18207–18213, 2003. View at Publisher · View at Google Scholar · View at Scopus
  9. R. A. Radu, N. L. Mata, A. Bagla, and G. H. Travis, “Light exposure stimulates formation of A2E oxiranes in a mouse model of Stargardt's macular degeneration,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 16, pp. 5928–5933, 2004. View at Publisher · View at Google Scholar · View at Scopus
  10. Y. Kuse, K. Ogawa, K. Tsuruma, M. Shimazawa, and H. Hara, “Damage of photoreceptor-derived cells in culture induced by light emitting diode-derived blue light,” Scientific Reports, vol. 4, article 5223, 2014. View at Publisher · View at Google Scholar · View at Scopus
  11. G. K. Jain, M. H. Warsi, J. Nirmal et al., “Therapeutic stratagems for vascular degenerative disorders of the posterior eye,” Drug Discovery Today, vol. 17, no. 13-14, pp. 748–759, 2012. View at Publisher · View at Google Scholar · View at Scopus
  12. H. Ahsan, “Diabetic retinopathy—biomolecules and multiple pathophysiology,” Diabetes and Metabolic Syndrome: Clinical Research and Reviews, vol. 9, no. 1, pp. 51–54, 2015. View at Publisher · View at Google Scholar · View at Scopus
  13. M. P. Cabrera and R. H. Chihuailaf, “Antioxidants and the integrity of ocular tissues,” Veterinary Medicine International, vol. 2011, Article ID 905153, 8 pages, 2011. View at Publisher · View at Google Scholar · View at Scopus
  14. J. T. Handa, “How does the macula protect itself from oxidative stress?” Molecular Aspects of Medicine, vol. 33, no. 4, pp. 418–435, 2012. View at Publisher · View at Google Scholar · View at Scopus
  15. S. G. Jarrett and M. E. Boulton, “Consequences of oxidative stress in age-related macular degeneration,” Molecular Aspects of Medicine, vol. 33, no. 4, pp. 399–417, 2012. View at Publisher · View at Google Scholar · View at Scopus
  16. J. G. Hollyfield, V. L. Bonilha, M. E. Rayborn et al., “Oxidative damage-induced inflammation initiates age-related macular degeneration,” Nature Medicine, vol. 14, no. 2, pp. 194–198, 2008. View at Publisher · View at Google Scholar · View at Scopus
  17. E. Y. Chew, T. E. Clemons, E. Agrón, L. J. Launer, F. Grodstein, and P. S. Bernstein, “Effect of omega-3 fatty acids, lutein/zeaxanthin, or other nutrient supplementation on cognitive function: the AREDS2 randomized clinical trial,” The Journal of the American Medical Association, vol. 314, no. 8, pp. 791–801, 2015. View at Publisher · View at Google Scholar · View at Scopus
  18. M. A. Babizhayev, “New concept in nutrition for the maintenance of the aging eye redox regulation and therapeutic treatment of cataract disease; Synergism of natural antioxidant imidazole-containing amino acid-based compounds, chaperone, and glutathione boosting agents: a systemic perspective on aging and longevity emerged from studies in humans,” American Journal of Therapeutics, vol. 17, no. 4, pp. 373–389, 2010. View at Publisher · View at Google Scholar · View at Scopus
  19. E. L. Berson, B. Rosner, M. A. Sandberg et al., “Clinical trial of lutein in patients with retinitis pigmentosa receiving vitamin A,” Archives of Ophthalmology, vol. 128, no. 4, pp. 403–411, 2010. View at Publisher · View at Google Scholar · View at Scopus
  20. W. T. Wong, W. Kam, D. Cunningham et al., “Treatment of geographic atrophy by the topical administration of OT-551: results of a phase II clinical trial,” Investigative Ophthalmology & Visual Science, vol. 51, no. 12, pp. 6131–6139, 2010. View at Publisher · View at Google Scholar · View at Scopus
  21. K. Itoh, J. Mimura, and M. Yamamoto, “Discovery of the negative regulator of Nrf2, keap1: a historical overview,” Antioxidants and Redox Signaling, vol. 13, no. 11, pp. 1665–1678, 2010. View at Publisher · View at Google Scholar · View at Scopus
  22. T. Suzuki, H. Motohashi, and M. Yamamoto, “Toward clinical application of the Keap1-Nrf2 pathway,” Trends in Pharmacological Sciences, vol. 34, no. 6, pp. 340–346, 2013. View at Publisher · View at Google Scholar · View at Scopus
  23. S. Ruiz, P. E. Pergola, R. A. Zager, and N. D. Vaziri, “Targeting the transcription factor Nrf2 to ameliorate oxidative stress and inflammation in chronic kidney disease,” Kidney International, vol. 83, no. 6, pp. 1029–1041, 2013. View at Publisher · View at Google Scholar · View at Scopus
  24. J. D. Wardyn, A. H. Ponsford, and C. M. Sanderson, “Dissecting molecular cross-talk between Nrf2 and NF-κB response pathways,” Biochemical Society Transactions, vol. 43, pp. 621–626, 2015. View at Publisher · View at Google Scholar · View at Scopus
  25. I. Rahman, “Antioxidant therapies in COPD,” International Journal of Chronic Obstructive Pulmonary Disease, vol. 1, no. 1, pp. 15–29, 2006. View at Google Scholar · View at Scopus
  26. M. Suzuki, T. Betsuyaku, Y. Ito et al., “Down-regulated NF-E2-related factor 2 in pulmonary macrophages of aged smokers and patients with chronic obstructive pulmonary disease,” American Journal of Respiratory Cell and Molecular Biology, vol. 39, no. 6, pp. 673–682, 2008. View at Publisher · View at Google Scholar · View at Scopus
  27. Q. Zhong, M. Mishra, and R. A. Kowluru, “Transcription factor Nrf2-mediated antioxidant defense system in the development of diabetic retinopathy,” Investigative Ophthalmology & Visual Science, vol. 54, no. 6, pp. 3941–3948, 2013. View at Publisher · View at Google Scholar · View at Scopus
  28. M. L. Lambros and S. M. Plafker, “Oxidative stress and the Nrf2 anti-oxidant transcription factor in age-related macular degeneration,” Advances in Experimental Medicine and Biology, vol. 854, pp. 67–72, 2016. View at Publisher · View at Google Scholar · View at Scopus
  29. K. Itoh, T. Chiba, S. Takahashi et al., “An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements,” Biochemical and Biophysical Research Communications, vol. 236, no. 2, pp. 313–322, 1997. View at Publisher · View at Google Scholar · View at Scopus
  30. K. Chan, R. Lu, J. C. Chang, and Y. W. Kan, “NRF2, a member of the NFE2 family of transcription factors, is not essential for murine erythropoiesis, growth, and development,” Proceedings of the National Academy of Sciences of the United States of America, vol. 93, no. 24, pp. 13943–13948, 1996. View at Publisher · View at Google Scholar · View at Scopus
  31. Z. Zhao, Y. Chen, J. Wang et al., “Age-related retinopathy in NRF2-deficient mice,” PLoS ONE, vol. 6, no. 4, article e19456, 2011. View at Publisher · View at Google Scholar · View at Scopus
  32. M. Cano, R. Thimmalappula, M. Fujihara et al., “Cigarette smoking, oxidative stress, the anti-oxidant response through Nrf2 signaling, and Age-related Macular Degeneration,” Vision Research, vol. 50, no. 7, pp. 652–664, 2010. View at Publisher · View at Google Scholar · View at Scopus
  33. K. Uno, T. W. Prow, I. A. Bhutto et al., “Role of Nrf2 in retinal vascular development and the vaso-obliterative phase of oxygen-induced retinopathy,” Experimental Eye Research, vol. 90, no. 4, pp. 493–500, 2010. View at Publisher · View at Google Scholar · View at Scopus
  34. N. Himori, K. Yamamoto, K. Maruyama et al., “Critical role of Nrf2 in oxidative stress-induced retinal ganglion cell death,” Journal of Neurochemistry, vol. 127, no. 5, pp. 669–680, 2013. View at Publisher · View at Google Scholar · View at Scopus
  35. Z. Xu, Y. Wei, J. Gong et al., “NRF2 plays a protective role in diabetic retinopathy in mice,” Diabetologia, vol. 57, no. 1, pp. 204–213, 2014. View at Publisher · View at Google Scholar · View at Scopus
  36. N. Nagai, R. K. Thimmulappa, M. Cano et al., “Nrf2 is a critical modulator of the innate immune response in a model of uveitis,” Free Radical Biology and Medicine, vol. 47, no. 3, pp. 300–306, 2009. View at Publisher · View at Google Scholar · View at Scopus
  37. Y. Wei, J. Gong, T. Yoshida et al., “Nrf2 has a protective role against neuronal and capillary degeneration in retinal ischemia-reperfusion injury,” Free Radical Biology and Medicine, vol. 51, no. 1, pp. 216–224, 2011. View at Publisher · View at Google Scholar · View at Scopus
  38. N. Wakabayashi, K. Itoh, J. Wakabayashi et al., “Keap1-null mutation leads to postnatal lethality due to constitutive Nrf2 activation,” Nature Genetics, vol. 35, no. 3, pp. 238–245, 2003. View at Publisher · View at Google Scholar · View at Scopus
  39. H. Okawa, H. Motohashi, A. Kobayashi, H. Aburatani, T. W. Kensler, and M. Yamamoto, “Hepatocyte-specific deletion of the keap1 gene activates Nrf2 and confers potent resistance against acute drug toxicity,” Biochemical and Biophysical Research Communications, vol. 339, no. 1, pp. 79–88, 2006. View at Publisher · View at Google Scholar · View at Scopus
  40. T. W. Kensler, P. A. Egner, A. S. Agyeman et al., “Keap1-Nrf2 signaling: a target for cancer prevention by sulforaphane,” Topics in Current Chemistry, vol. 329, pp. 163–178, 2013. View at Publisher · View at Google Scholar · View at Scopus
  41. K. Takaya, T. Suzuki, H. Motohashi et al., “Validation of the multiple sensor mechanism of the Keap1-Nrf2 system,” Free Radical Biology and Medicine, vol. 53, no. 4, pp. 817–827, 2012. View at Publisher · View at Google Scholar · View at Scopus
  42. M. C. Lu, J. A. Ji, Z. Y. Jiang, and Q. D. You, “The Keap1-Nrf2-ARE pathway as a potential preventive and therapeutic target: an update,” Medicinal Research Reviews, vol. 36, no. 5, pp. 924–963, 2016. View at Publisher · View at Google Scholar
  43. C. A. Houghton, R. G. Fassett, and J. S. Coombes, “Sulforaphane and other nutrigenomic Nrf2 activators: can the clinician's expectation be matched by the reality?” Oxidative Medicine and Cellular Longevity, vol. 2016, Article ID 7857186, 17 pages, 2016. View at Publisher · View at Google Scholar · View at Scopus
  44. E. D. Deeks, “Dimethyl fumarate: a review in relapsing-remitting MS,” Drugs, vol. 76, no. 2, pp. 243–254, 2016. View at Publisher · View at Google Scholar · View at Scopus
  45. K. T. Liby and M. B. Sporn, “Synthetic oleanane triterpenoids: multifunctional drugs with a broad range of applications for prevention and treatment of chronic disease,” Pharmacological Reviews, vol. 64, no. 4, pp. 972–1003, 2012. View at Publisher · View at Google Scholar · View at Scopus
  46. K. T. Liby, M. M. Yore, and M. B. Sporn, “Triterpenoids and rexinoids as multifunctional agents for the prevention and treatment of cancer,” Nature Reviews Cancer, vol. 7, no. 5, pp. 357–369, 2007. View at Publisher · View at Google Scholar · View at Scopus
  47. P. E. Pergola, P. Raskin, R. D. Toto et al., “Bardoxolone methyl and kidney function in CKD with type 2 diabetes,” The New England Journal of Medicine, vol. 365, no. 4, pp. 327–336, 2011. View at Publisher · View at Google Scholar · View at Scopus
  48. D. de Zeeuw, T. Akizawa, P. Audhya et al., “Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease,” The New England Journal of Medicine, vol. 369, no. 26, pp. 2492–2503, 2013. View at Publisher · View at Google Scholar · View at Scopus
  49. M. P. Chin, S. A. Reisman, G. L. Bakris et al., “Mechanisms contributing to adverse cardiovascular events in patients with type 2 diabetes mellitus and stage 4 chronic kidney disease treated with bardoxolone methyl,” American Journal of Nephrology, vol. 39, no. 6, pp. 499–508, 2014. View at Publisher · View at Google Scholar · View at Scopus
  50. H. E. Abboud, “Synthetic oleanane triterpenoids: magic bullets or not?” Kidney International, vol. 83, no. 5, pp. 785–787, 2013. View at Publisher · View at Google Scholar · View at Scopus
  51. I. Pitha-Rowe, K. Liby, D. Royce, and M. Sporn, “Synthetic triterpenoids attenuate cytotoxic retinal injury: cross-talk between Nrf2 and PI3K/AKT signaling through inhibition of the lipid phosphatase PTEN,” Investigative Ophthalmology and Visual Science, vol. 50, no. 11, pp. 5339–5347, 2009. View at Publisher · View at Google Scholar · View at Scopus
  52. T. E. Sussan, T. Rangasamy, D. J. Blake et al., “Targeting Nrf2 with the triterpenoid CDDO-imidazolide attenuates cigarette smoke-induced emphysema and cardiac dysfunction in mice,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 1, pp. 250–255, 2009. View at Publisher · View at Google Scholar · View at Scopus
  53. Y. Nakagami, K. Masuda, E. Hatano et al., “Novel Nrf2 activators from microbial transformation products inhibit blood-retinal barrier permeability in rabbits,” British Journal of Pharmacology, vol. 172, no. 5, pp. 1237–1249, 2015. View at Publisher · View at Google Scholar · View at Scopus
  54. Y. Nakagami, E. Hatano, T. Inoue, K. Yoshida, M. Kondo, and H. Terasaki, “Cytoprotective effects of a novel Nrf2 activator, RS9, in rhodopsin Pro347Leu rabbits,” Current Eye Research, vol. 41, no. 8, pp. 1123–1126, 2016. View at Publisher · View at Google Scholar · View at Scopus
  55. H.-H. Shen, E. C. Chan, J. H. Lee et al., “Nanocarriers for treatment of ocular neovascularization in the back of the eye: new vehicles for ophthalmic drug delivery,” Nanomedicine, vol. 10, no. 13, pp. 2093–2107, 2015. View at Publisher · View at Google Scholar · View at Scopus
  56. N. Kuno and S. Fujii, “Biodegradable intraocular therapies for retinal disorders: progress to date,” Drugs and Aging, vol. 27, no. 2, pp. 117–134, 2010. View at Publisher · View at Google Scholar · View at Scopus
  57. G. Wells, “Peptide and small molecule inhibitors of the Keap1-Nrf2 protein-protein interaction,” Biochemical Society Transactions, vol. 43, pp. 674–679, 2015. View at Publisher · View at Google Scholar · View at Scopus
  58. D. A. Abed, M. Goldstein, H. Albanyan, H. Jin, and L. Hu, “Discovery of direct inhibitors of Keap1-Nrf2 protein-protein interaction as potential therapeutic and preventive agents,” Acta Pharmaceutica Sinica B, vol. 5, no. 4, pp. 285–299, 2015. View at Publisher · View at Google Scholar · View at Scopus
  59. K. I. Tong, B. Padmanabhan, A. Kobayashi et al., “Different electrostatic potentials define ETGE and DLG motifs as hinge and latch in oxidative stress response,” Molecular and Cellular Biology, vol. 27, no. 21, pp. 7511–7521, 2007. View at Publisher · View at Google Scholar · View at Scopus
  60. L. Hu, S. Magesh, L. Chen et al., “Discovery of a small-molecule inhibitor and cellular probe of Keap1-Nrf2 protein-protein interaction,” Bioorganic and Medicinal Chemistry Letters, vol. 23, no. 10, pp. 3039–3043, 2013. View at Publisher · View at Google Scholar · View at Scopus
  61. R. Shimozono, Y. Asaoka, Y. Yoshizawa et al., “Nrf2 activators attenuate the progression of nonalcoholic steatohepatitis-related fibrosis in a dietary rat models,” Molecular Pharmacology, vol. 84, no. 1, pp. 62–70, 2013. View at Publisher · View at Google Scholar · View at Scopus
  62. P. Canning and A. N. Bullock, “New strategies to inhibit KEAP1 and the Cul3-based E3 ubiquitin ligases,” Biochemical Society Transactions, vol. 42, no. 1, pp. 103–107, 2014. View at Publisher · View at Google Scholar · View at Scopus
  63. A. Kobayashi, M.-I. Kang, H. Okawa et al., “Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2,” Molecular and Cellular Biology, vol. 24, no. 16, pp. 7130–7139, 2004. View at Publisher · View at Google Scholar · View at Scopus
  64. M. Furukawa and Y. Xiong, “BTB protein keap1 targets antioxidant transcription factor Nrf2 for ubiquitination by the cullin 3-Roc1 ligase,” Molecular and Cellular Biology, vol. 25, no. 1, pp. 162–171, 2005. View at Publisher · View at Google Scholar · View at Scopus
  65. K. Itoh, N. Wakabayashi, Y. Katoh, T. Ishii, T. O'Connor, and M. Yamamoto, “Keap1 regulates both cytoplasmic-nuclear shuttling and degradation of Nrf2 in response to electrophiles,” Genes to Cells, vol. 8, no. 4, pp. 379–391, 2003. View at Publisher · View at Google Scholar · View at Scopus
  66. E. C. R. Solano, D. J. Kornbrust, A. Beaudry, J. W.-D. Foy, D. J. Schneider, and J. D. Thompson, “Toxicological and pharmacokinetic properties of QPI-1007, a chemically modified synthetic siRNA targeting caspase 2 mRNA, following intravitreal injection,” Nucleic Acid Therapeutics, vol. 24, no. 4, pp. 258–266, 2014. View at Publisher · View at Google Scholar · View at Scopus
  67. P. J. Morgan-Warren, J. O’Neill, F. De Cogan et al., “SiRNA-mediated knockdown of the mTOR inhibitor RTP801 promotes retinal ganglion cell survival and axon elongation by direct and indirect mechanisms,” Investigative Ophthalmology and Visual Science, vol. 57, no. 2, pp. 429–443, 2016. View at Publisher · View at Google Scholar · View at Scopus
  68. J. D. Hayes and M. McMahon, “NRF2 and KEAP1 mutations: permanent activation of an adaptive response in cancer,” Trends in Biochemical Sciences, vol. 34, no. 4, pp. 176–188, 2009. View at Publisher · View at Google Scholar · View at Scopus