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Inflammation

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Nobiletin Protects from Renal Ischemia-Reperfusion Injury in Rats by Suppressing Inflammatory Cytokines and Regulating iNOS-eNOS Expressions

  • Mehmet GüvençEmail author
  • Mustafa Cellat
  • Ahmet Uyar
  • Hüseyin Özkan
  • İshak Gokcek
  • Cafer Tayer İsler
  • Akın Yakan
Original Article
  • 4 Downloads

Abstract

Ischemia-reperfusion injury is an organ failure caused by hypoxia and reperfusion, which is closely associated with oxidative stress and inflammation. In this study, we investigated whether nobiletin had protective effects on inflammatory parameters, oxidative damage, iNOS-eNOS expressions, and histopathological structure of renal tissue in rats with renal ischemia-reperfusion injury. For this purpose, 24 rats were divided into 4 groups: group 1 (Control), group 2 (Ischemia-Reperfusion-IR), group 3 (Nobiletin-10 mg/kg p.o.), group 4 (Nobiletin + IR). The study was continued for 7 days. At the end of the study, urea (p < 0.05), creatine (p < 0.05), MDA (p < 0.001), TNF-alpha (p < 0.001), IL-1 beta (p < 0.05), and IL-6 (p < 0.001) levels increased in the IR group; however, a significant decrease occurred in group 4 (Nobiletin + IR) and it reached the control group levels. In the IR group, GSH (p < 0.01) levels, and GSH.Px (p < 0.01) and CAT (p < 0.05) activities decreased whereas they increased significantly in group 4 (Nobiletin + IR) and reached the same levels as the control group. In histopathological analyses, destruction and increased iNOS-eNOS expressions in the IR group showed a significant decrease in group 4 (Nobiletin + IR). As a result, the application of nobiletin has shown that it has protective effects by reducing kidney damage caused by IR injury.

KEY WORDS

ischemia-reperfusion nobiletin iNOS-eNOS inflammation 

Notes

Funding Information

This work was financially supported with project number of 17.M.005 (Hatay MKU BAP).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Zhang, Zhu-Xu, Shuang Wang, Xuyan Huang, Wei-Ping Min, Hongtao Sun, Weihua Liu, Bertha Garcia, and Anthony M. Jevnikar. 2008. NK cells induce apoptosis in tubular epithelial cells and contribute to renal ischemia-reperfusion injury. The Journal of Immunology 181 (11): 7489–7498.PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Mohey, Vinita, Manjinder Singh, Nikkita Puri, Tajpreet Kaur, Devendra Pathak, and Amrit Pal Singh. 2016. Sildenafil obviates ischemia-reperfusion injury–induced acute kidney injury through peroxisome proliferator–activated receptor γ agonism in rats. Journal of Surgical Research 201 (1): 69–75.PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    Lien, Yeong-Hau H., Li-Wen Lai, and Arnold L. Silva. 2003. Pathogenesis of renal ischemia/reperfusion injury: Lessons from knockout mice. Life Sciences 74 (5): 543–552.PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    Rosin, Diane L., and Mark D. Okusa. 2011. Dangers within: DAMP responses to damage and cell death in kidney disease. Journal of the American Society of Nephrology 22 (3): 416–425.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Paller, Mark S. 1994. The cell biology of reperfusion injury in the kidney. Journal of Investigative Medicine 42: 632–639.PubMedPubMedCentralGoogle Scholar
  6. 6.
    Williams, Patricia, Henry Lopez, Deborah Britt, Christine Chan, Alan Ezrin, and Rod Hottendorf. 1997. Characterization of renal ischemia-reperfusion injury in rats. Journal of Pharmacological and Toxicological Methods 37 (1): 1–7.PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Bonventre, Joseph V., and Li Yang. 2011. Cellular pathophysiology of ischemic acute kidney injury. The Journal of Clinical Investigation 121 (11): 4210–4221.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    da Costa, Marcus Felipe Bezerra, Alexandre Braga Libório, Flávio Teles, Conceição da Silva Martins, Pedro Marcos Gomes Soares, Gdayllon C. Meneses, Francisco Adelvane de Paulo Rodrigues, Luzia Kalyne Almeida Moreira Leal, Diogo Miron, and Aline Holanda Silva. 2015. Red propolis ameliorates ischemic-reperfusion acute kidney injury. Phytomedicine 22 (9): 787–795.PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Yuk, Taewon, Younghwa Kim, Jinwoo Yang, Jeehye Sung, Heon Sang Jeong, and Junsoo Lee. 2018. Nobiletin inhibits hepatic lipogenesis via activation of AMP-activated protein kinase. Evidence-based Complementary and Alternative Medicine: 2018.Google Scholar
  10. 10.
    Lin, Na, Takashi Sato, Yuji Takayama, Yoshihiro Mimaki, Yutaka Sashida, Masamichi Yano, and Akira Ito. 2003. Novel anti-inflammatory actions of nobiletin, a citrus polymethoxy flavonoid, on human synovial fibroblasts and mouse macrophages. Biochemical Pharmacology 65 (12): 2065–2071.PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    Jang, Se-Eun, Kwon-Ryeol Ryu, Sung-Hwan Park, Suna Chung, Yuto Teruya, Myung Joo Han, Je-Tae Woo, and Dong-Hyun Kim. 2013. Nobiletin and tangeretin ameliorate scratching behavior in mice by inhibiting the action of histamine and the activation of NF-κB, AP-1 and p38. International Immunopharmacology 17 (3): 502–507.PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Choi, Soo-Youn, Joon-Ho Hwang, Hee-Chul Ko, Ji-Gweon Park, and Se-Jae Kim. 2007. Nobiletin from citrus fruit peel inhibits the DNA-binding activity of NF-κB and ROS production in LPS-activated RAW 264.7 cells. Journal of Ethnopharmacology 113 (1): 149–155.PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Liu, Libin, and Xing wei Wu. 2018. Nobiletin protects human retinal pigment epithelial cells from hydrogen peroxide–induced oxidative damage. Journal of Biochemical and Molecular Toxicology 32 (5): e22052.PubMedCrossRefPubMedCentralGoogle Scholar
  14. 14.
    Bi, Junying, Haiyan Zhang, Jing Lu, and Weifu Lei. 2016. Nobiletin ameliorates isoflurane-induced cognitive impairment via antioxidant, anti-inflammatory and anti-apoptotic effects in aging rats. Molecular Medicine Reports 14 (6): 5408–5414.PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    Suzuki, Rikako, Hiroyuki Kohno, Akira Murakami, Koichi Koshimizu, Hajime Ohigashi, Masamichi Yano, Harukuni Tokuda, Hoyoku Nishino, and Takuji Tanaka. 2004. Citrus nobiletin inhibits azoxymethane-induced large bowel carcinogenesis in rats. Biofactors 21 (1-4): 111–114.CrossRefGoogle Scholar
  16. 16.
    Chen, Chen, Misaki Ono, Mikako Takeshima, and Shuji Nakano. 2014. Antiproliferative and apoptosis-inducing activity of nobiletin against three subtypes of human breast cancer cell lines. Anticancer Research 34 (4): 1785–1792.PubMedPubMedCentralGoogle Scholar
  17. 17.
    Yoshimizu, N., Y. Otani, Y. Saikawa, T. Kubota, M. Yoshida, Furukawa Toshiharu, K. Kumai, Kameyama Kaori, M. Fujii, and M. Yano. 2004. Anti-tumour effects of nobiletin, a citrus flavonoid, on gastric cancer include: Antiproliferative effects, induction of apoptosis and cell cycle deregulation. Alimentary Pharmacology & Therapeutics 20: 95–101.CrossRefGoogle Scholar
  18. 18.
    Miyata, Yoshiki, Takashi Sato, Masamichi Yano, and Akira Ito. 2004. Activation of protein kinase C βII/ε-c-Jun NH2-terminal kinase pathway and inhibition of mitogen-activated protein/extracellular signal-regulated kinase 1/2 phosphorylation in antitumor invasive activity induced by the polymethoxy flavonoid, nobiletin. Molecular Cancer Therapeutics 3 (7): 839–847.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Lu, Yan-hua, Su Ming-yuan, Hai-ya Huang, and Cai-gen Yuan. 2010. Protective effects of the citrus flavanones to PC12 cells against cytotoxicity induced by hydrogen peroxide. Neuroscience Letters 484 (1): 6–11.PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Yao, Xiaolin, Xinrong Zhu, Siyi Pan, Yapeng Fang, Fatang Jiang, Glyn O. Phillips, and Xiaoyun Xu. 2012. Antimicrobial activity of nobiletin and tangeretin against Pseudomonas. Food Chemistry 132 (4): 1883–1890.CrossRefGoogle Scholar
  21. 21.
    Takii, Miki, Yukiko K. Kaneko, Kiriko Akiyama, Yuki Aoyagi, Yuki Tara, Tomohiro Asakawa, Makoto Inai, Toshiyuki Kan, Kiyomitsu Nemoto, and Tomohisa Ishikawa. 2017. Insulinotropic and anti-apoptotic effects of nobiletin in INS-1D β-cells. Journal of Functional Foods 30: 8–15.CrossRefGoogle Scholar
  22. 22.
    Lee, Young-Sil, Byung-Yoon Cha, Sun-Sil Choi, Bong-Keun Choi, Takayuki Yonezawa, Toshiaki Teruya, Kazuo Nagai, and Je-Tae Woo. 2013. Nobiletin improves obesity and insulin resistance in high-fat diet-induced obese mice. The Journal of Nutritional Biochemistry 24 (1): 156–162.PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Lone, Jameel, Hilal Ahmad Parray, and Jong Won Yun. 2018. Nobiletin induces brown adipocyte-like phenotype and ameliorates stress in 3T3-L1 adipocytes. Biochimie 146: 97–104.PubMedCrossRefPubMedCentralGoogle Scholar
  24. 24.
    Placer, Zdenek A., Linda L. Cushman, and B. Connor Johnson. 1966. Estimation of product of lipid peroxidation (malonyl dialdehyde) in biochemical systems. Analytical Biochemistry 16 (2): 359–364.PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Sedlak, Jozef, and Raymond H. Lindsay. 1968. Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman’s reagent. Analytical Biochemistry 25: 192–205.PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    Lawrence, Richard A., and Raymond F. Burk. 1976. Glutathione peroxidase activity in selenium-deficient rat liver. Biochemical and Biophysical Research Communications 71 (4): 952–958.PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Aebi, H.E. 1983. Catalase. Methods of enzymatic analysis.Google Scholar
  28. 28.
    Lowry, Oliver H., Nira J. Rosebrough, A. Lewis Farr, and Rose J. Randall. 1951. Protein measurement with the Folin phenol reagent. Journal of Biological Chemistry 193: 265–275.PubMedPubMedCentralGoogle Scholar
  29. 29.
    Bi, Wei, Fengan Wang, Yue Bi, Tianyang Wang, Ping Xue, Yanrong Zhang, Xiang Gao, Sanguang Liu, Zhibo Wang, and Meng Li. 2009. Renal ischemia/reperfusion injury in rats is attenuated by a synthetic glycine derivative. European Journal of Pharmacology 616 (1-3): 256–264.PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Chen, Yen-Ta, Tzu-Hsien Tsai, Chih-Chau Yang, Cheuk-Kwan Sun, Li-Teh Chang, Hung-Hwa Chen, Chia-Lo Chang, Pei-Hsun Sung, Yen-Yi Zhen, and Steve Leu. 2013. Exendin-4 and sitagliptin protect kidney from ischemia-reperfusion injury through suppressing oxidative stress and inflammatory reaction. Journal of Translational Medicine 11 (1): 270.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Gobe, Glenda, Xiao-Ju Zhang, Desley A. Willgoss, Estelle Schoch, Nicole A. Hogg, and Zoltan H. Endre. 2000. Relationship between expression of Bcl-2 genes and growth factors in ischemic acute renal failure in the rat. Journal of the American Society of Nephrology 11 (3): 454–467.PubMedGoogle Scholar
  32. 32.
    Yang, Kang, Wei-Fang Li, Jun-Feng Yu, Yi Cheng, and Wei-Feng Huang. 2017. Diosmetin protects against ischemia/reperfusion-induced acute kidney injury in mice. Journal of Surgical Research 214: 69–78.PubMedCrossRefGoogle Scholar
  33. 33.
    Gholampour, Hanieh, Leila Moezi, and Hamed Shafaroodi. 2017. Aripiprazole prevents renal ischemia/reperfusion injury in rats, probably through nitric oxide involvement. European Journal of Pharmacology 813: 17–23.PubMedCrossRefGoogle Scholar
  34. 34.
    Chu, Changbin, Weiyang He, Youlin Kuang, Ke Ren, and Xin Gou. 2014. Celastrol protects kidney against ischemia–reperfusion-induced injury in rats. Journal of Surgical Research 186 (1): 398–407.PubMedCrossRefGoogle Scholar
  35. 35.
    Guan, Weiwei, Zhen Wang, Yukai Liu, Han Yu, Hongmei Ren, Wei Eric Wang, Jian Yang, Zhou Lin, and Chunyu Zeng. 2015. Protective effects of tirofiban on ischemia/reperfusion-induced renal injury in vivo and in vitro. European Journal of Pharmacology 761: 144–152.PubMedCrossRefGoogle Scholar
  36. 36.
    Wu, Yakun, Wenfeng Zhang, Min Li, Ding Cao, Xiaoli Yang, and Jianping Gong. 2017. Nobiletin ameliorates ischemia–reperfusion injury by suppressing the function of Kupffer cells after liver transplantation in rats. Biomedicine & Pharmacotherapy 89: 732–741.CrossRefGoogle Scholar
  37. 37.
    Li, Weifeng, Xiumei Wang, Wenbing Zhi, Hailin Zhang, Zehong He, Wang Yu, Fang Liu, Xiaofeng Niu, and Xuemei Zhang. 2017. The gastroprotective effect of nobiletin against ethanol-induced acute gastric lesions in mice: Impact on oxidative stress and inflammation. Immunopharmacology and Immunotoxicology 39 (6): 354–363.PubMedCrossRefGoogle Scholar
  38. 38.
    Kang, Sang Rim, Kwang Il Park, Hyeon Soo Park, Do Hoon Lee, Jin A. Kim, Arulkumar Nagappan, Eun Hee Kim, Won Sup Lee, Sung Chul Shin, and Moon Ki Park. 2011. Anti-inflammatory effect of flavonoids isolated from Korea Citrus aurantium L. on lipopolysaccharide-induced mouse macrophage RAW 264.7 cells by blocking of nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signalling pathways. Food Chemistry 129 (4): 1721–1728.CrossRefGoogle Scholar
  39. 39.
    Han, Feng, Xin-xin Xia, Yu-xiang Wang, Wu-Jun Xue, Xiao-Ming Ding, Jin Zheng, Chen-guang Ding, and Pu-Xun Tian. 2018. Arctigenin: A two-edged sword in ischemia/reperfusion induced acute kidney injury. Biomedicine & Pharmacotherapy 103: 1127–1136.CrossRefGoogle Scholar
  40. 40.
    Raup-Konsavage, Wesley M., Ting Gao, Timothy K. Cooper, Sidney M. Morris Jr., W. Brian Reeves, and Alaa S. Awad. 2017. Arginase-2 mediates renal ischemia-reperfusion injury. American Journal of Physiology - Renal Physiology 313 (2): F522–F534.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Yang, Guliang, Chi-Chen Lin, Li Yuan, Peilei Wang, Yiwen Yang, Xiang Wen, Hui Zhao, Chi-Tang Ho, and Shiming Li. 2019. Nobiletin prevents TMAO-induced vascular oxidative stress in rats. Journal of Food Bioactives 5: 131–135.CrossRefGoogle Scholar
  42. 42.
    Chatterjee, Prabal K., Nimesh S.A. Patel, Espen O. Kvale, Salvatore Cuzzocrea, Paul A.J. Brown, Keith N. Stewart, Helder Mota-Filipe, and Christoph Thiemermann. 2002. Inhibition of inducible nitric oxide synthase reduces renal ischemia/reperfusion injury. Kidney International 61 (3): 862–871.PubMedCrossRefPubMedCentralGoogle Scholar
  43. 43.
    Förstermann, Ulrich, and William C. Sessa. 2011. Nitric oxide synthases: regulation and function. European Heart Journal 33 (7): 829–837.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Chatterjee, Prabal K. 2007. Novel pharmacological approaches to the treatment of renal ischemia-reperfusion injury: A comprehensive review. Naunyn-Schmiedeberg's Archives of Pharmacology 376 (1-2): 1–43.PubMedCrossRefPubMedCentralGoogle Scholar
  45. 45.
    Walker, Lisa M., Patrick D. Walker, Syed Z. Imam, Syed F. Ali, and Philip R. Mayeux. 2000. Evidence for Peroxynitrite Formation in Renal Ischemia-Reperfusion Injury: Studies with the Inducible Nitric Oxide Synthase Inhibitorl-N 6-(1-Iminoethyl) lysine. Journal of Pharmacology and Experimental Therapeutics 295 (1): 417–422.PubMedPubMedCentralGoogle Scholar
  46. 46.
    Chang, Wei-Luen, Ching-Hu Chung, Yang-Chang Wu, and Su. Ming-Jai. 2004. The vascular and cardioprotective effects of liriodenine in ischemia–reperfusion injury via NO-dependent pathway. Nitric Oxide 11 (4): 307–315.PubMedCrossRefPubMedCentralGoogle Scholar
  47. 47.
    Lentsch, A.B., and P.A. Ward. 2002. Ischemia/reperfusion injury. The Journal of Surgical Research 105: 248–258.PubMedCrossRefPubMedCentralGoogle Scholar
  48. 48.
    Lowenstein, Charles J., Jay L. Dinerman, and Solomon H. Snyder. 1994. Nitric oxide: A physiologic messenger. Annals of Internal Medicine 120 (3): 227–237.PubMedCrossRefPubMedCentralGoogle Scholar
  49. 49.
    Szocs, K. 2004. Endothelial dysfunction and reactive oxygen species production in ischemia/reperfusion and nitrate tolerance. General Physiology and Biophysics 23: 265–296.PubMedPubMedCentralGoogle Scholar
  50. 50.
    Kenan Kinaci, M., Nilufer Erkasap, Aysegul Kucuk, Tulay Koken, and Murat Tosun. 2012. Effects of quercetin on apoptosis, NF-κB and NOS gene expression in renal ischemia/reperfusion injury. Experimental and Therapeutic Medicine 3 (2): 249–254.PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Li, Shiming, Shengmin Sang, Min-Hsiung Pan, Ching-Shu Lai, Chih-Yu Lo, Chung S. Yang, and Chi-Tang Ho. 2007. Anti-inflammatory property of the urinary metabolites of nobiletin in mouse. Bioorganic & Medicinal Chemistry Letters 17 (18): 5177–5181.CrossRefGoogle Scholar
  52. 52.
    Brady, H.R., and G.G. Singer. 1995. Acute renal failure. The Lancet 346 (8989): 1533–1540.  https://doi.org/10.1016/S0140-6736(95)92057-9.CrossRefGoogle Scholar
  53. 53.
    Conesa, Erica López, Fernando Valero, José Carlos Nadal, Francisco J. Fenoy, Bernardo López, Begoña Arregui, and Miguel García Salom. 2001. N-acetyl-L-cysteine improves renal medullary hypoperfusion in acute renal failure. American Journal of Physiology - Regulatory, Integrative and Comparative Physiology 281 (3): R730–R737.PubMedCrossRefPubMedCentralGoogle Scholar
  54. 54.
    Özdamar, Mustafa Yaşar, Müslim Yurtçu, Hatice Toy, Mehmet Aköz, and Engin Günel. 2010. Renal iskemi-reperfüzyon hasarında üzüm çekirdeği proantosiyanidin ekstresinin etkisi. Genel Tıp Derg 20: 1–5.Google Scholar
  55. 55.
    Ozkan, Gulsum, Sukru Ulusoy, Asım Orem, Safak Ersoz, Mehmet Alkanat, Fulya Balaban Yucesan, Kubra Kaynar, and Sait Al. 2012. Protective effect of the grape seed proanthocyanidin extract in a rat model of contrast-induced nephropathy. Kidney and Blood Pressure Research 35 (6): 445–453.PubMedCrossRefPubMedCentralGoogle Scholar
  56. 56.
    Yildiz, Fahrettin, Sacit Coban, Alpaslan Terzi, Murat Savas, Muharrem Bitiren, Hakim Celik, and Nurten Aksoy. 2010. Protective effects of Nigella sativa against ischemia-reperfusion injury of kidneys. Renal Failure 32 (1): 126–131.PubMedCrossRefPubMedCentralGoogle Scholar
  57. 57.
    Maghsoudi, S., A. Gol, S. Dabiri, and A. Javadi. 2011. Preventive effect of ginger (Zingiber officinale) pretreatment on renal ischemia-reperfusion in rats. European Surgical Research 46 (1): 45–51.PubMedCrossRefPubMedCentralGoogle Scholar

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Authors and Affiliations

  1. 1.Mustafa Kemal University, Faculty of Veterinary Medicine, Department of PhysiologyAntakyaTurkey
  2. 2.Mustafa Kemal University, Faculty of Veterinary Medicine, Department of PathologyAntakyaTurkey
  3. 3.Mustafa Kemal University, Faculty of Veterinary Medicine, Department of GeneticsAntakyaTurkey
  4. 4.Mustafa Kemal University, Faculty of Veterinary Medicine, Department SurgeryAntakyaTurkey

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