Salutary Effect of Pre-Treatment With an Nrf2 Inducer on Ischemia Reperfusion Injury in The Rat Liver

Yuichi Masuda, Nostratola D. Vaziri, Chie Takasu, Shiri LI, Lourdes Robles, Lourdes Robles, Christine Pham, Christine Pham, Aimee Le, Aimee Le, Kelly Vo, Kelly Vo, Seyed H. Farzaneh, Seyed H. Farzaneh, Michael J Stamos, Michael J Stamos, Hirohito Ichii, Hirohito Ichii

Abstract


BACKGROUND: Ischemia–reperfusion injury (IRI) is a common phenomenon occurring during liver surgery, transplantation, and trauma. IRI causes oxidative stress which plays a critical role in causing organ damage. The Nrf2 is the master regulator of numerous genes, encoding antioxidant, detoxifying, and cytoprotective molecules. Nrf2 dysfunction has been implicated in the pathogenesis of several inflammatory disorders, cancer, and aging. This study was undertaken to investigate the effect of Nrf2 pathway activator (dh404) on warm liver IRI in a rodent model.
METHODS: Ten Sprague-Dawley rats were treated with dh404 or vehicle. Dh404 was dissolved in sesame oil and was given orally (1.5mg/kg) the night before and 5 hours before procedures. Rat livers were subjected to 60 minutes of 70% ischemia followed by 3 hours of reperfusion. Serum ALT and Malondialdehyde (MDA) were determined and liver tissue was processed for histological examination, and determination of apoptosis, myeloperoxidase (MPO) activity, ADP/ATP ratio, and expressions of Nrf2, eNOS, anti-oxidant enzymes, and inflammatory mediators.
RESULTS: Serum ALT and MDA levels and tissue MPO activity were significantly lower, expression of the anti-oxidant enzyme, glutamate cysteine ligase was significantly higher, whereas expression of NFkB and COX-2 was unchanged in the dh404-treated group. Although the total Suzuki histology score did not 

differ significantly, the extent of sinusoidal congestion, vacuolization, and apoptosis was significantly reduced in the dh404 treated compared to the untreated group (P<0.01).
CONCLUSION: Pre-treatment with dh404 resulted in partial attenuation of hepatic ischemia reperfusion injury in rats.


Keywords


Liver; Ischemia reperfusion injury; Reactive oxygen species; Oxidative stress; Bardoxolone methyl analogue; Inflammation

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References


[1] Baskin-Bey, E. S, Washburn , K, Feng S, Oltersdorf, T., Shapiro, D., Huyghe, M., et al. (2007). Clinical trial of the pan-caspase inhibitor, IDN-6556, in Human liver preservation injury. Am J Transplant, 7(1), 218-25.

[2] Wang, J., Kan, Q., Li, J., Zhang, X., & Qi, Y. (2011). Effect of neferine on liver ischemia-reperfusion injury in rats. Transplant Proc., 43(7), 2536-9.

[3] Busuttil, R. (2007). Liver ischaemia and reperfusion injury. Br J Surg., 94(7), 787-8.

[4] Tsung, A., Sahai, R., Tanaka, H., Nakao, A., Fink, M. P., & Lotze, M. T., et al. (2005). The nuclear factor HMGB1 mediates hepatic injury after murine liver ischemia-reperfusion. J Exp Med., 201(7), 1135-43. PMCID: 2213120.

[5] Andrews, N. C., Erdjument-Bromage, H., Davidson, M. B., Tempst, P., & Orkin, S. H. (1993). Erythroid transcription factor NF-E2 is a haematopoietic-specific basic-leucine zipper protein. Nature, 362(6422), 722-8.

[6] Lee, J. M., Li, J., Johnson, D. A., Stein, T. D., Kraft, A. D., & Calkins, M. J., et al. (2005). Nrf2, a multi-organ protector? FASEB J., 19(9), 1061-6.

[7] Lister, A., Nedjadi, T., Kitteringham, N. R., Campbell, F., Costello, E., & Lloyd, B., et al. (2011). Nrf2 is overexpressed in pancreatic cancer: implications for cell proliferation and therapy. Mol Cancer, 10, 37. PMCID: 3098205.

[8] Kim, H. J., & Vaziri, N. D. (2010). Contribution of impaired Nrf2-Keap1 pathway to oxidative stress and inflammation in chronic renal failure. Am J Physiol Renal Physiol, 298(3), F662-71.

[9] Zhao, C. R., Gao, Z. H., & Qu, X. J. (2010). Nrf2-ARE signaling pathway and natural products for cancer chemoprevention. Cancer Epidemiol, 34(5), 523-33.

[10] Ke, B., Shen, X. D., Zhang, Y., Ji, H., Gao, F., & Yue, S., et al. (2013). KEAP1-NRF2 complex in ischemia-induced hepatocellular damage of mouse liver transplants. J Hepatol., 59(6), 1200-7.

[11] Aminzadeh, M. A., Reisman, S. A., Vaziri, N. D., Khazaeli, M., Yuan, J., & Meyer, C. J. (2014). The synthetic triterpenoid RTA dh404 (CDDO-dhTFEA) restores Nrf2 activity and attenuates oxidative stress, inflammation, and fibrosis in rats with chronic kidney disease. Xenobiotica, 44(6), 570-8.

[12] Mendes-Braz, M., Elias-Miro, M., Jimenez-Castro, M. B., Casillas-Ramirez, A., Ramalho, F. S., & Peralta, C. (2012). The current state of knowledge of hepatic ischemia-reperfusion injury based on its study in experimental models. J Biomed Biotechnol, 298657. PMCID: 3357607.

[13] Palladini, G., Ferrigno, A., Rizzo, V., Boncompagni, E., Richelmi, P., & Freitas, I., et al. (2012). Lobe-specific heterogeneity and matrix metalloproteinase activation after ischemia/reperfusion injury in rat livers. Toxicol Pathol., 40(5), 722-30.

[14] Liang, R., Nickkholgh, A., Kern, M., Schneider, H., Benzing, S., & Zorn, M., et al. (2011). Green tea extract ameliorates reperfusion injury to rat livers after warm ischemia in a dose-dependent manner. Mol Nutr Food Res., 55(6), 855-63.

[15] Suzuki, S., Nakamura, S., Koizumi, T., Sakaguchi, S., Baba, S., & Muro, H., et al. (1991). The beneficial effect of a prostaglandin I2 analog on ischemic rat liver. Transplantation, 52(6), 979-83.

[16] Sun, K., Liu, Z. S., & Sun, Q. (2004). Role of mitochondria in cell apoptosis during hepatic ischemia-reperfusion injury and protective effect of ischemic postconditioning. World Journal of Gastroenterology : WJG, 10(13), 1934-8.

[17] Mullane, K. M., Kraemer, R., & Smith, B. (1985). Myeloperoxidase activity as a quantitative assessment of neutrophil infiltration into ischemic myocardium. J Pharmacol Methods, 14(3), 157-67.

[18] Liby, K., Hock, T., Yore, M. M., Suh, N., Place, A. E., & Risingsong, R., et al. (2005). The synthetic triterpenoids, CDDO and CDDO-imidazolide, are potent inducers of heme oxygenase-1 and Nrf2/ARE signaling. Cancer Res., 65(11), 4789-98.

[19] Sporn, M. B., Liby, K. T., Yore, M. M., Fu, L., Lopchuk, J. M., & Gribble, G.W. (2011). New synthetic triterpenoids: Potent agents for prevention and treatment of tissue injury caused by inflammatory and oxidative stress. J Nat Prod., 74(3), 537-45. PMCID: 3064114.

[20] Pergola, P. E., Raskin, P., Toto, R. D., Meyer, C. J., Huff, J. W., & Grossman, E. B, et al. (2011). Bardoxolone methyl and kidney function in CKD with type 2 diabetes. N Engl J Med., 365(4), 327-36.

[21] Bataille, A. M., Manautou, J. E. (2012). Nrf2: A potential target for new therapeutics in liver disease. Clin Pharmacol Ther., 92(3), 340-8. PMCID: 3704160.

[22] Wu, J., Liu, X. H., Fan, J. J., Chen, W. F., Wang, J., & Zeng, Y. J., et al. (2014). Bardoxolone methyl (BARD) ameliorates aristolochic acid (AA)-induced acute kidney injury through Nrf2 pathway. Toxicology, 318, 22-31.

[23] Lu, S. C. (2013). Glutathione synthesis. Biochim Biophys Acta. 1830(5), 3143-53. PMCID: 3549305.

[24] Klaassen, C. D., & Reisman, S. A. (2010). Nrf2 the rescue: Effects of the antioxidative/electrophilic response on the liver. Toxicol Appl Pharmacol, 244(1), 57-65. PMCID: 2860427.




DOI: http://dx.doi.org/10.3968/gh.v1i1.5206

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