Abstract
We aimed to evaluate the functions of long non-coding RNA taurine upregulated gene 1 (lncRNA TUG1) in renal ischemia-reperfusion (I/R) injury and identify the potential mechanisms. Pathological changes of renal tissues were examined using H&E staining after mimic renal I/R injury in vivo. The contents of serum renal functional parameters and inflammatory factors were measured. The expression of TUG1 and miR-449b-5p in renal tissues and HK-2 cells stimulated by I/R were detected. Then, the effects of TUG1 silencing on inflammation and apoptosis of cells were evaluated. Dual luciferase reporter assays were executed for determining the correlation between miR-449b-5p and TUG1, high mobility group box 1 (HMGB1), or matrix metalloproteinase 2 (MMP2). Subsequently, cells were co-transfected with miR-449b-5p mimic and pcDNA3.1 TUG1. The levels of inflammation, apoptosis, and the expression of HMGB1 and MMP2 were detected. The results revealed that renal tissues were obviously damaged after I/R accompanied by changes in renal functional markers and inflammatory factors. TUG1 was highly expressed whereas miR-449b-5p was lowly expressed. TUG1 silencing reduced the inflammation and apoptosis. Dual luciferase reporter assays confirmed that miR-449b-5p was a target of TUG1 as well as HMGB1 and MMP2 were direct targets of miR-449b-5p. Meanwhile, miR-449b-5p mimic presented the same results with TUG1 silencing, which were reversed after TUG1 overexpression. Moreover, MMP2 and HMGB1 expression was decreased after miR-449b-5p overexpression while that of was increased after TUG1 overexpression. These findings demonstrated that TUG1 silencing attenuates I/R-induced inflammation and apoptosis via targeting miR-449b-5p and regulating HMGB1 and MMP2 expression.
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Amini, N., A. Sarkaki, M. Dianat, S.A. Mard, A. Ahangarpour, and M. Badavi. 2019. The renoprotective effects of naringin and trimetazidine on renal ischemia/reperfusion injury in rats through inhibition of apoptosis and downregulation of micoRNA-10a. Biomedicine & Pharmacotherapy 112: 8. https://doi.org/10.1016/j.biopha.2019.01.029.
Chen, C.B., L.S. Liu, J. Zhou, X.P. Wang, M. Han, X.Y. Jiao, X.S. He, and X.P. Yuan. 2017. Up-regulation of HMGB1 exacerbates renal ischemia-reperfusion injury by stimulating inflammatory and immune responses through the TLR4 signaling pathway in mice. Cellular Physiology and Biochemistry 41 (6): 2447–2460. https://doi.org/10.1159/000475914.
Chen, L.L., and J.C. Zhao. 2014. Functional analysis of long noncoding RNAs in development and disease. Advances in Experimental Medicine and Biology 825: 129–158. https://doi.org/10.1007/978-1-4939-1221-6_4.
Chen, S.C., M.D. Wang, H. Yang, L. Mao, Q.W. He, H.J. Jin, Z.M. Ye, X.Y. Luo, Y.P. Xia, and B. Hu. 2017. LncRNA TUG1 sponges microRNA-9 to promote neurons apoptosis by up-regulated Bcl2l11 under ischemia. Biochemical and Biophysical Research Communications 485 (1): 167–173. https://doi.org/10.1016/j.bbrc.2017.02.043.
Diao, C., L. Wang, H. Liu, Y. Du, and X. Liu. 2019. Aged kidneys are refractory to autophagy activation in a rat model of renal ischemia-reperfusion injury. Clinical Interventions in Aging 14: 525–534. https://doi.org/10.2147/CIA.S197444.
Gong, J.C., and X.Z. Wang. 2018. Schisantherin A protects renal tubular epithelial cells from hypoxia/reoxygenation injury through the activation of PI3K/Akt signaling pathway. Journal of Biochemical and Molecular Toxicology 32 (7): 7. https://doi.org/10.1002/jbt.22160.
Grams, M.E., M.M. Estrella, J. Coresh, R.G. Brower, K.D. Liu, and Lung National Heart, and Network Blood Institute Acute Respiratory Distress Syndrome. 2011. Fluid balance, diuretic use, and mortality in acute kidney injury. Clinical Journal of the American Society of Nephrology 6 (5): 966–973. https://doi.org/10.2215/CJN.08781010.
Gutschner, T., and S. Diederichs. 2012. The hallmarks of cancer: a long non-coding RNA point of view. RNA Biology 9 (6): 703–719. https://doi.org/10.4161/rna.20481.
Han, Yonghua, Yuchen Liu, Yaoting Gui, and Zhiming Cai. 2013. Long intergenic non-coding RNA TUG1 is overexpressed in urothelial carcinoma of the bladder. Journal of Surgical Oncology 107 (5): 555–559. https://doi.org/10.1002/jso.23264.
Havasi, A., and S.C. Borkan. 2011. Apoptosis and acute kidney injury. Kidney International 80 (1): 29–40. https://doi.org/10.1038/ki.2011.120.
Helgadottir, S., M.I. Sigurdsson, R. Palsson, D. Helgason, G.H. Sigurdsson, and T. Gudbjartsson. 2016. Renal recovery and long-term survival following acute kidney injury after coronary artery surgery: a nationwide study. Acta Anaesthesiologica Scandinavica 60 (9): 1230–1240. https://doi.org/10.1111/aas.12758.
Huang, L., B. Y. Guo, S. Y. Liu, C. L. Miao, and Y. J. Li. Inhibition of the LncRNA Gpr19 attenuates ischemia-reperfusion injury after acute myocardial infarction by inhibiting apoptosis and oxidative stress via the miR-324-5p/Mtfr1 axis. IUBMB Life:11. https://doi.org/10.1002/iub.2187.
Jiang, X.X., D.T. Li, W. Shen, X.G. Shen, and Y.M. Liu. 2019. LncRNA NEAT1 promotes hypoxia-induced renal tubular epithelial apoptosis through downregulating miR-27a-3p. Journal of Cellular Biochemistry 120 (9): 16273–16282. https://doi.org/10.1002/jcb.28909.
Ke, Y.J., H.H. Yan, L.W. Chen, S. Zhong, Y.T. Dai, S.S. Cai, L.T. Pan, Y. Wang, and M. Zhou. 2019. Apoptosis repressor with caspase recruitment domain deficiency accelerates ischemia/reperfusion (I/R)-induced acute kidney injury by suppressing inflammation and apoptosis: the role of AKT/mTOR signaling. Biomedicine & Pharmacotherapy 112: 8. https://doi.org/10.1016/j.biopha.2019.108681.
Kim, Y., D.C. Kim, E.S. Cho, S.O. Ko, W.Y. Kwon, G.J. Suh, and H.K. Shin. 2014. Antioxidant and anti-inflammatory effects of selenium in oral buccal mucosa and small intestinal mucosa during intestinal ischemia-reperfusion injury. Journal Inflammation (Lond) 11 (1): 36. https://doi.org/10.1186/s12950-014-0036-1.
Kirsch, D.G., A. Doseff, B.N. Chau, D.S. Lim, N.C. de Souza-Pinto, R. Hansford, M.B. Kastan, Y.A. Lazebnik, and J.M. Hardwick. 1999. Caspase-3-dependent cleavage of Bcl-2 promotes release of cytochrome c. The Journal of Biological Chemistry 274 (30): 21155–21161. https://doi.org/10.1074/jbc.274.30.21155.
Lameire, N.H., A. Bagga, D. Cruz, J. De Maeseneer, Z. Endre, J.A. Kellum, K.D. Liu, et al. 2013. Acute kidney injury: an increasing global concern. Lancet 382 (9887): 170–179. https://doi.org/10.1016/S0140-6736(13)60647-9.
Lee, D., S. Park, S. Bae, D. Jeong, M. Park, C. Kang, W. Yoo, M.A. Samad, Q. Ke, G. Khang, and P.M. Kang. 2015. Hydrogen peroxide-activatable antioxidant prodrug as a targeted therapeutic agent for ischemia-reperfusion injury. Scientific Reports 5: 16592. https://doi.org/10.1038/srep16592.
Li, J., M. Zhang, G. An, and Q.F. Ma. 2016. LncRNA TUG1 acts as a tumor suppressor in human glioma by promoting cell apoptosis. Experimental Biology and Medicine 241 (6): 644–649. https://doi.org/10.1177/1535370215622708.
Li, Z., X. Deng, Z. Kang, Y. Wang, T. Xia, N. Ding, and Y. Yin. 2016. Elevation of miR-21, through targeting MKK3, may be involved in ischemia pretreatment protection from ischemia-reperfusion induced kidney injury. Journal of Nephrology 29 (1): 27–36. https://doi.org/10.1007/s40620-015-0217-x.
Linkermann, A., G. Chen, G. Dong, U. Kunzendorf, S. Krautwald, and Z. Dong. 2014. Regulated cell death in AKI. J Am Soc Nephrol 25 (12): 2689–2701. https://doi.org/10.1681/ASN.2014030262.
Liu, H., L. Wang, X.D. Weng, H. Chen, Y. Du, C.H. Diao, Z.Y. Chen, and X.H. Liu. 2019. Inhibition of Brd4 alleviates renal ischemia/reperfusion injury-induced apoptosis and endoplasmic reticulum stress by blocking FoxO4-mediated oxidative stress. Redox Biology 24: 13. https://doi.org/10.1016/j.redox.2019.101195.
Nagata, Y., M. Fujimoto, K. Nakamura, N. Isoyama, M. Matsumura, K. Fujikawa, K. Uchiyama, et al. 2016. Anti-TNF-alpha agent infliximab and splenectomy are protective against renal ischemia-reperfusion injury. Transplantation 100 (8): 1675–1682. https://doi.org/10.1097/TP.0000000000001222.
Nieuwenhuijs-Moeke, G.J., V.B. Nieuwenhuijs, M.A.J. Seelen, S.P. Berger, M.C. van den Heuvel, J.G.M. Burgerhof, P.J. Ottens, R.J. Ploeg, H.G.D. Leuvenink, and Mmrf Struys. 2017. Propofol-based anaesthesia versus sevoflurane-based anaesthesia for living donor kidney transplantation: results of the VAPOR-1 randomized controlled trial. British Journal of Anaesthesia 118 (5): 720–732. https://doi.org/10.1093/bja/aex057.
Nusshag, C., M.A. Weigand, M. Zeier, C. Morath, and T. Brenner. 2017. Issues of acute kidney injury staging and management in sepsis and critical illness: a narrative review. International Journal of Molecular Sciences 18 (7). https://doi.org/10.3390/ijms18071387.
Perez-Meseguer, J., L. Torres-Gonzalez, J.A. Gutierrez-Gonzalez, G. Alarcon-Galvan, H. Zapata-Chavira, N. Waksman-de Torres, D.P. Moreno-Pena, L.E. Munoz-Espinosa, and P. Cordero-Perez. 2019. Anti-inflammatory and nephroprotective activity of Juglans mollis against renal ischemia-reperfusion damage in a Wistar rat model. BMC Complementary and Alternative Medicine 19 (1): 186–189. https://doi.org/10.1186/s12906-019-2604-7.
Qian, X., Y. Du, G. Jiang, F. Lin, and L. Yao. 2019. Survival motor neuron (SMN) protein insufficiency exacerbates renal ischemia/reperfusion injury. Frontiers in Physiology 10: 559. https://doi.org/10.3389/fphys.2019.00559.
Sharfuddin, A.A., and B.A. Molitoris. 2011. Pathophysiology of ischemic acute kidney injury. Nature Reviews. Nephrology 7 (4): 189–200. https://doi.org/10.1038/nrneph.2011.16.
Shen, B.B., M. Mei, Y.M. Pu, H.H. Zhang, H. Liu, M.Z. Tang, Q.G. Pan, Y. He, X.F. Wu, and H.W. Zhao. 2019. Necrostatin-1 attenuates renal ischemia and reperfusion injury via meditation of HIF-1 alpha/mir-26a/TRPC6/PARP1 signaling. Molecular Therapy-Nucleic Acids 17: 701–713. https://doi.org/10.1016/j.omtn.2019.06.025.
Shen, Y., Y. Zhao, L.J. Wang, W.J. Zhang, C. Liu, and A.P. Yin. 2019. MicroRNA-194 overexpression protects against hypoxia/reperfusion-induced HK-2 cell injury through direct targeting Rheb. Journal of Cellular Biochemistry 120 (5): 8311–8318. https://doi.org/10.1002/jcb.28114.
Su, Q., Y. Liu, X.W. Lv, Z.L. Ye, Y.H. Sun, B.H. Kong, and Z.B. Qin. 2019. Inhibition of lncRNA TUG1 upregulates miR-142-3p to ameliorate myocardial injury during ischemia and reperfusion via targeting HMGB1-and Rac1-induced autophagy. Journal of Molecular and Cellular Cardiology 133: 12–25. https://doi.org/10.1016/j.yjmcc.2019.05.021.
Sun, X., H. Zeng, Q. Wang, Q. Yu, J. Wu, Y. Feng, P. Deng, and H. Zhang. 2018. Glycyrrhizin ameliorates inflammatory pain by inhibiting microglial activation-mediated inflammatory response via blockage of the HMGB1-TLR4-NF-kB pathway. Experimental Cell Research 369 (1): 112–119. https://doi.org/10.1016/j.yexcr.2018.05.012.
Sun, Y., L.R. Xun, G. Jin, and L. Shi. 2018. Salidroside protects renal tubular epithelial cells from hypoxia/reoxygenation injury in vitro. Journal of Pharmacological Sciences 137 (2): 170–176. https://doi.org/10.1016/j.jphs.2018.05.011.
Swanton, E., P. Savory, S. Cosulich, P. Clarke, and P. Woodman. 1999. Bcl-2 regulates a caspase-3/caspase-2 apoptotic cascade in cytosolic extracts. Oncogene 18 (10): 1781–1787. https://doi.org/10.1038/sj.onc.1202490.
Tian, H.Z., R.M. Tan, B.G. Ye, S.J. Yan, M.X. Sui, W.Y. Zhao, L. Zhang, Y.H. Zhu, and L. Zeng. 2019. SHP-1 inhibits renal ischemia reperfusion injury via dephosphorylating ASK1 and suppressing apoptosis. Biochemical and Biophysical Research Communications 513 (2): 360–367. https://doi.org/10.1016/j.bbrc.2019.03.187.
Tsaroucha, A.K., G. Valsami, N. Kostomitsopoulos, M. Lambropoulou, C. Anagnostopoulos, E. Christodoulou, E. Falidas, A. Betsou, M. Pitiakoudis, and C.E. Simopoulos. 2018. Silibinin effect on Fas/FasL, HMGB1, and CD45 expressions in a rat model subjected to liver ischemia-reperfusion injury. Journal of Investigative Surgery 31 (6): 491–502. https://doi.org/10.1080/08941939.2017.1360416.
Wang, L.P., J.P. Wang, and X.P. Wang. 2018. HOTAIR contributes to the growth of liver cancer via targeting miR-217. Oncology Letters 15 (5): 7963–7972. https://doi.org/10.3892/ol.2018.8341.
Wang, Q., J.N. Xu, X.L. Li, Z.J. Liu, Y. Han, X.G. Xu, X.B. Li, et al. 2019. Sirt3 modulate renal ischemia-reperfusion injury through enhancing mitochondrial fusion and activating the ERK-OPA1 signaling pathway. Journal of Cellular Physiology 234 (12): 23495–23506. https://doi.org/10.1002/jcp.28918.
Yang, H., R.Z. Li, L. Zhang, S. Zhang, W. Dong, Y.H. Chen, W.D. Wang, et al. 2019. p53-cyclophilin D mediates renal tubular cell apoptosis in ischemia-reperfusion-induced acute kidney injury. American Journal of Physiology-Renal Physiology 317 (5): F1311–F1317. https://doi.org/10.1152/ajprenal.00072.2019.
Yao, L., X. Lv, and X.H. Wang. 2016. MicroRNA 26a inhibits HMGB1 expression and attenuates cardiac ischemia-reperfusion injury. Journal of Pharmacological Sciences 131 (1): 6–12. https://doi.org/10.1016/j.jphs.2015.07.023.
Yue, P.J., L.J. Jing, X.Y. Zhao, H.C. Zhu, and J.F. Teng. 2019. Down-regulation of taurine-up-regulated gene 1 attenuates inflammation by sponging miR-9-5p via targeting NF-kappa B1/p50 in multiple sclerosis. Life Sciences 233: 10. https://doi.org/10.1016/j.lfs.2019.116731.
Zeng, G.Y., W.J. Ding, Y. Li, M.Y. Sun, and L.Y. Deng. 2018. Morroniside protects against cerebral ischemia/reperfusion injury by inhibiting neuron apoptosis and MMP2/9 expression. Experimental and Therapeutic Medicine 16 (3): 2229–2234. https://doi.org/10.3892/etm.2018.6457.
Zhang, H., H. Li, A. Ge, E. Guo, S. Liu, and L. Zhang. 2018. Long non-coding RNA TUG1 inhibits apoptosis and inflammatory response in LPS-treated H9c2 cells by down-regulation of miR-29b. Biomedicine & Pharmacotherapy 101: 663–669. https://doi.org/10.1016/j.biopha.2018.02.129.
Zhang, M., W. Lu, Y. Huang, J. Shi, X. Wu, X. Zhang, R. Jiang, Z. Cai, and S. Wu. 2016. Downregulation of the long noncoding RNA TUG1 inhibits the proliferation, migration, invasion and promotes apoptosis of renal cell carcinoma. Journal of Molecular Histology 47 (4): 421–428. https://doi.org/10.1007/s10735-016-9683-2.
Zhang, Q., P.L. Geng, P. Yin, X.L. Wang, J.P. Jia, and J. Yao. 2013. Down-regulation of long non-coding RNA TUG1 inhibits osteosarcoma cell proliferation and promotes apoptosis. Asian Pacific Journal of Cancer Prevention 14 (4): 2311–2315.
Zhang, Y., J.R. Lv, G. Wu, W. Li, Z.N. Zhang, W.S. Li, and X.M. Lei. 2019. MicroRNA-449b-5p targets HMGB1 to attenuate hepatocyte injury in liver ischemia and reperfusion. Journal of Cellular Physiology 234 (9): 16367–16375. https://doi.org/10.1002/jcp.28305.
Zhu, R., W. Wang, and S.X. Yang. 2019. Cryptotanshinone inhibits hypoxia/reoxygenation-induced oxidative stress and apoptosis in renal tubular epithelial cells. Journal of Cellular Biochemistry 120 (8): 13354–13360. https://doi.org/10.1002/jcb.28609.
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This work was supported by Education department of guizhou province young science and technology talent development project, Grant/Award Number: KY [2018]190; 2018 Academic new seedling cultivation and innovation exploration project of Guizhou Medical University, Grant/Award Number: [2018]5779-47.
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Xu, Y., Niu, Y., Li, H. et al. Downregulation of lncRNA TUG1 attenuates inflammation and apoptosis of renal tubular epithelial cell induced by ischemia-reperfusion by sponging miR-449b-5p via targeting HMGB1 and MMP2. Inflammation 43, 1362–1374 (2020). https://doi.org/10.1007/s10753-020-01214-z
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DOI: https://doi.org/10.1007/s10753-020-01214-z