Hou Ling, Chen Gang, Feng Biao, Zhang Xu-Sheng, Zheng Xiu-Fen, Xiang Ying, Zhao Guang-Yuan, Min Wei-Ping
Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
J Huazhong Univ Sci Technolog Med Sci. 2016 Oct;36(5):634-638. doi: 10.1007/s11596-016-1638-z. Epub 2016 Oct 18.
Tumor necrosis factor-alpha (TNF-α) has been found to be centrally involved in the development of ischemia-reperfusion injury (IRI)-induced inflammation and apoptosis. Knockdown of TNF-α gene using small interfering RNA (siRNA) may protect renal IRI. Renal IRI was induced in mice by clamping the left renal pedicle for 25 or 35 min. TNF-α siRNA was administered intravenously to silence the expression of TNF-α. The therapeutic effects of siRNA were evaluated in terms of renal function, histological examination, and overall survival following lethal IRI. A single systemic injection of TNF-α siRNA resulted in significant knockdown of TNF-α expression in ischemia-reperfusion injured kidney. In comparison with control mice, levels of BUN and serum creatinine were significantly reduced in mice treated with siRNA. Pathological examination demonstrated that tissue damage caused by IRI was markedly reduced as a result of TNF-α siRNA treatment. Furthermore, survival experiments showed that nearly 90% of control mice died from lethal IRI, whereas more than 50% of siRNApretreated mice survived until the end of the eight-day observation period. We have demonstrated for the first time that silencing TNF-α by specific siRNA can significantly reduce renal IRI and protect mice against lethal kidney ischemia, highlighting the potential for siRNA-based clinical therapy.
肿瘤坏死因子-α（TNF-α）已被发现与缺血再灌注损伤（IRI）诱导的炎症和细胞凋亡的发生密切相关。使用小干扰RNA（siRNA）敲低TNF-α基因可能对肾IRI起到保护作用。通过夹闭左肾蒂25或35分钟在小鼠中诱导肾IRI。静脉注射TNF-α siRNA以沉默TNF-α的表达。从肾功能、组织学检查以及致死性IRI后的总体生存率方面评估siRNA的治疗效果。单次全身注射TNF-α siRNA导致缺血再灌注损伤肾脏中TNF-α表达显著降低。与对照小鼠相比，用siRNA处理的小鼠血尿素氮和血清肌酐水平显著降低。病理检查表明，由于TNF-α siRNA处理，IRI引起的组织损伤明显减轻。此外，生存实验表明，近90%的对照小鼠死于致死性IRI，而超过50%的经siRNA预处理的小鼠存活至8天观察期结束。我们首次证明，通过特异性siRNA沉默TNF-α可显著减轻肾IRI并保护小鼠免受致死性肾脏缺血损伤，突出了基于siRNA的临床治疗的潜力。
