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Ellagic Acid Ameliorates Renal Ischemic-Reperfusion Injury Through NOX4/JAK/STAT Signaling Pathway

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Ellagic acid (EA), a natural polyphenolic compound, has been proved to possess multiple biological activities including alleviating ischemic-reperfusion (I/R) injury. The aim of this current study was to investigate whether EA alleviates I/R injury via regulating inflammatory signaling pathway. Rats were subjected to ischemic-reperfusion (I/R) injury and given orally with different doses of EA before surgery. H&E staining, ELISA assay, and biochemical index analysis were performed to evaluate renal injury and inflammatory factors. Oxidative stress level was detected by DCFH-DA staining and corresponding assay kits. In addition, TUNEL assay and flow cytometric assay were applied for exploring the apoptosis of tissue and cells, respectively. Western blot assay was used to assess protein expressions in tissue and cells. The results showed that EA attenuated the renal I/R injury and reserved renal cell function in vivo. The levels of TNF-a, IL-1β, IL-6, and MCP-1, oxidative stress level, and apoptosis were suppressed in EA-treated rats. Mechanistic studies showed that EA suppressed the phosphorylation of JAK1, JAK2, and STAT1 and reduced the NOX4 level. EA reduced apoptosis, hypoxia-induced inflammatory response, and ROS levels. Moreover, overexpression of NOX4 reversed the protective function with NOX4 inhibition, indicating that the effect of EA against renal IRI or cell hypoxia/reoxygenation might mainly depend on NOX4. The results suggest that EA exerts the renoprotective effect via suppressing NOX4/JAK/STAT signaling pathway, which may be a novel potential therapy for the treatment of acute kidney injury in clinic.

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  1. Levey, A.S., and M.T. James. 2017. Acute kidney injury. Annals of Internal Medicine 167: Itc66–itc80.

    Article  Google Scholar 

  2. Yoshida, T., H. Kumagai, T. Kohsaka, and N. Ikegaya. 2013. Relaxin protects against renal ischemia-reperfusion injury. American Journal of Physiology. Renal Physiology 305: F1169–F1176.

    Article  CAS  Google Scholar 

  3. Friedewald, J.J., and H. Rabb. 2004. Inflammatory cells in ischemic acute renal failure. Kidney International 66: 486–491.

    Article  Google Scholar 

  4. Goncalves, G.M., A. Castoldi, T.T. Braga, and N.O. Camara. 2011. New roles for innate immune response in acute and chronic kidney injuries. Scandinavian Journal of Immunology 73: 428–435.

    Article  CAS  Google Scholar 

  5. Gluba, A., M. Banach, S. Hannam, D.P. Mikhailidis, A. Sakowicz, and J. Rysz. 2010. The role of Toll-like receptors in renal diseases. Nature Reviews. Nephrology 6: 224–235.

    Article  CAS  Google Scholar 

  6. Yang, Q., F.R. Wu, J.N. Wang, L. Gao, L. Jiang, H.D. Li, Q. Ma, X.Q. Liu, B. Wei, L. Zhou, J. Wen, T.T. Ma, J. Li, and X.M. Meng. 2018. Nox4 in renal diseases: An update. Free Radical Biology & Medicine 124: 466–472.

    Article  CAS  Google Scholar 

  7. Ihle, J.N. 1995. Cytokine receptor signalling. Nature 377: 591–594.

    Article  CAS  Google Scholar 

  8. Lin, H.W., J.W. Thompson, K.C. Morris, and M.A. Perez-Pinzon. 2011. Signal transducers and activators of transcription: STATs-mediated mitochondrial neuroprotection. Antioxidants & Redox Signaling 14: 1853–1861.

    Article  CAS  Google Scholar 

  9. Hanada, T., and A. Yoshimura. 2002. Regulation of cytokine signaling and inflammation. Cytokine & Growth Factor Reviews 13: 413–421.

    Article  CAS  Google Scholar 

  10. Kim, S.Y., K.A. Moon, H.Y. Jo, S. Jeong, S.H. Seon, E. Jung, Y.S. Cho, E. Chun, and K.Y. Lee. 2012. Anti-inflammatory effects of apocynin, an inhibitor of NADPH oxidase, in airway inflammation. Immunology and Cell Biology 90: 441–448.

    Article  CAS  Google Scholar 

  11. Day, C. 1998. Traditional plant treatments for diabetes mellitus: pharmaceutical foods. The British Journal of Nutrition 80: 5–6.

    Article  CAS  Google Scholar 

  12. Zhou, B.H., Z.P. Qiu, H.L. Yi, D.S. Zhou, J. Wang, and Y. Wu. 2016. Research progress of ellagitannin intestinal metabolite urolithins. Zhongguo Zhong Yao Za Zhi 41: 2968–2974.

    PubMed  Google Scholar 

  13. Rogerio, A.P., C. Fontanari, M.C. Melo, S.R. Ambrosio, G.E. de Souza, P.S. Pereira, S.C. Franca, F.B. da Costa, D.A. Albuquerque, and L.H. Faccioli. 2006. Anti-inflammatory, analgesic and anti-oedematous effects of Lafoensia pacari extract and ellagic acid. The Journal of Pharmacy and Pharmacology 58: 1265–1273.

    Article  CAS  Google Scholar 

  14. Jordao, J.B.R., H.K.P. Porto, F.M. Lopes, A.C. Batista, and M.L. Rocha. 2017. Protective effects of ellagic acid on cardiovascular injuries caused by hypertension in rats. Planta Medica 83: 830–836.

    Article  CAS  Google Scholar 

  15. Ahmed, T., W.N. Setzer, S.F. Nabavi, I.E. Orhan, N. Braidy, E. Sobarzo-Sanchez, and S.M. Nabavi. 2016. Insights into effects of ellagic acid on the nervous system: a mini review. Current Pharmaceutical Design 22: 1350–1360.

    Article  CAS  Google Scholar 

  16. Boyuk, A., A. Onder, M. Kapan, M. Gumus, U. Fiotarat, M.K. Basaraliota, and H. Alp. 2011. Ellagic acid ameliorates lung injury after intestinal ischemia-reperfusion. Pharmacognosy Magazine 7: 224–228.

    Article  CAS  Google Scholar 

  17. Iino, T., K. Tashima, M. Umeda, Y. Ogawa, M. Takeeda, K. Takata, and K. Takeuchi. 2002. Effect of ellagic acid on gastric damage induced in ischemic rat stomachs following ammonia or reperfusion. Life Sciences 70: 1139–1150.

    Article  CAS  Google Scholar 

  18. Sayar, I., S. Bicer, C. Gursul, M. Gurbuzel, K. Peker, and A. Isik. 2016. Protective effects of ellagic acid and ozone on rat ovaries with an ischemia/reperfusion injury. The Journal of Obstetrics and Gynaecology Research 42: 52–58.

    Article  CAS  Google Scholar 

  19. Bozkurt, Yasar, Ugur Firat, Murat Atar, Ahmet Ali Sancaktutar, Necmettin Pembegul, Haluk Soylemez, Hatice Yuksel, Harun Alp, Mehmet Nuri Bodakci, Namik Kemal Hatipoglu, and Sadik Buyukbas. 2012. The protective effect of ellagic acid against renal ischemia-reperfusion injury in male rats. Kafkas Üniversitesi Veteriner Fakültesi Dergisi 18: 823–828.

    Google Scholar 

  20. Kumagai, Y., J. Sobajima, M. Higashi, T. Ishiguro, M. Fukuchi, K. Ishibashi, E. Mochiki, K. Yakabi, T. Kawano, J. Tamaru, and H. Ishida. 2015. Coexpression of COX-2 and iNOS in angiogenesis of superficial esophageal squamous cell carcinoma. International Surgery 100: 733–743.

    Article  Google Scholar 

  21. Suschek, C.V., O. Schnorr, and V. Kolb-Bachofen. 2004. The role of iNOS in chronic inflammatory processes in vivo: is it damage-promoting, protective, or active at all? Current Molecular Medicine 4: 763–775.

    Article  CAS  Google Scholar 

  22. Zhang, X., J. Cao, and L. Zhong. 2009. Hydroxytyrosol inhibits pro-inflammatory cytokines, iNOS, and COX-2 expression in human monocytic cells. Naunyn-Schmiedeberg's Archives of Pharmacology 379: 581–586.

    Article  CAS  Google Scholar 

  23. Cho, H., C.W. Yun, W.K. Park, J.Y. Kong, K.S. Kim, Y. Park, S. Lee, and B.K. Kim. 2004. Modulation of the activity of pro-inflammatory enzymes, COX-2 and iNOS, by chrysin derivatives. Pharmacological Research 49: 37–43.

    Article  CAS  Google Scholar 

  24. Qi, M., L. Zheng, Y. Qi, X. Han, Y. Xu, L. Xu, L. Yin, C. Wang, Y. Zhao, H. Sun, K. Liu, and J. Peng. 2015. Dioscin attenuates renal ischemia/reperfusion injury by inhibiting the TLR4/MyD88 signaling pathway via up-regulation of HSP70. Pharmacological Research 100: 341–352.

    Article  CAS  Google Scholar 

  25. Jiang, G., X. Liu, M. Wang, H. Chen, Z. Chen, and T. Qiu. 2015. Oxymatrine ameliorates renal ischemia-reperfusion injury from oxidative stress through Nrf2/HO-1 pathway. Acta Cirúrgica Brasileira 30: 422–429.

    Article  CAS  Google Scholar 

  26. O'Shea, J.J., D.M. Schwartz, A.V. Villarino, M. Gadina, I.B. McInnes, and A. Laurence. 2015. The JAK-STAT pathway: impact on human disease and therapeutic intervention. Annual Review of Medicine 66: 311–328.

    Article  CAS  Google Scholar 

  27. Villarino, A.V., Y. Kanno, and J.J. O'Shea. 2017. Mechanisms and consequences of Jak-STAT signaling in the immune system. Nature Immunology 18: 374–384.

    Article  CAS  Google Scholar 

  28. Coskun, M., M. Salem, J. Pedersen, and O.H. Nielsen. 2013. Involvement of JAK/STAT signaling in the pathogenesis of inflammatory bowel disease. Pharmacological Research 76: 1–8.

    Article  CAS  Google Scholar 

  29. Dodington, D.W., H.R. Desai, and M. Woo. 2018. JAK/STAT - Emerging players in metabolism. Trends in Endocrinology and Metabolism 29: 55–65.

    Article  CAS  Google Scholar 

  30. Heumuller, S., S. Wind, E. Barbosa-Sicard, H.H. Schmidt, R. Busse, K. Schroder, and R.P. Brandes. 2008. Apocynin is not an inhibitor of vascular NADPH oxidases but an antioxidant. Hypertension 51: 211–217.

    Article  Google Scholar 

  31. Byfield, G., S. Budd, and M.E. Hartnett. 2009. The role of supplemental oxygen and JAK/STAT signaling in intravitreous neovascularization in a ROP rat model. Investigative Ophthalmology & Visual Science 50: 3360–3365.

    Article  Google Scholar 

  32. Banes, A.K., S.M. Shaw, A. Tawfik, B.P. Patel, S. Ogbi, D. Fulton, and M.B. Marrero. 2005. Activation of the JAK/STAT pathway in vascular smooth muscle by serotonin. American Journal of Physiology. Cell Physiology 288: C805–C812.

    Article  CAS  Google Scholar 

  33. Gao, X., J. Sun, C. Huang, X. Hu, N. Jiang, and C. Lu. 2017. RNAi-mediated silencing of NOX4 inhibited the invasion of gastric cancer cells through JAK2/STAT3 signaling. American Journal of Translational Research 9: 4440–4449.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Rozentsvit, A., K. Vinokur, S. Samuel, Y. Li, A.M. Gerdes, and M.A. Carrillo-Sepulveda. 2017. Ellagic acid reduces high glucose-induced vascular oxidative stress through ERK1/2/NOX4 signaling pathway. Cellular Physiology and Biochemistry 44: 1174–1187.

    Article  CAS  Google Scholar 

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The work was supported by Guangdong Provincial Key Platform and Major Scientific Research Projects (grant no. 2017KTSCX214); Guangzhou Science and Technology Project (grant no. 201806020107); Xinhua Institute Teachers Research Fund Project of Sun Yat-sen University (grant no. 2019ZD002).

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Correspondence to Qiong Liu or Xuelan Wang.

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This study was approved by the Animal Care and Use Committee of SUN YAT-SEN University and conducted in accordance with the guidelines established by this committee.

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Liu, Q., Liang, X., Liang, M. et al. Ellagic Acid Ameliorates Renal Ischemic-Reperfusion Injury Through NOX4/JAK/STAT Signaling Pathway. Inflammation 43, 298–309 (2020).

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