The renal injury and inflammation caused by ischemia-reperfusion are reduced by genetic inhibition of TNF-αR1: A comparison with infliximab treatment
The renal injury and inflammation caused by ischemia-reperfusion are reduced by genetic inhibition of TNF-αR1: A comparison with infliximab treatment
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DOI：
10.1016/j.ejphar.2012.11.066
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发表时间：
2013-01-30
影响因子：
5
通讯作者：
Esposito, Emanuela
中科院分区：
文献类型：
--
作者：
Di Paola, Rosanna;Genovese, Tiziana;Esposito, Emanuela
肿瘤坏死因子（TNF）-α在肾缺血/再灌注（I/R）损伤的病理生理学中的作用尚不清楚。我们研究了TNF-α R1基因缺失和英夫利西单抗给药对I/R诱导的肾损伤程度的影响。对TNF-α R1敲除（TNF-α R1 KO）和野生型（TNF-α WT）小鼠进行双侧肾动脉闭塞（30分钟）和再灌注（24小时）。英夫利西单抗（10 mg/kg皮下，s.c.）缺血前1h给药。在实验结束时，测量尿素、肌酐、γ GT和AST以评估肾功能和再灌注损伤。检测氧化应激标志物、促炎介质、iNOS、考克斯-2和NF-κ B信号通路。检测肾脏髓过氧化物酶（MPO）活性和丙二醛（MDA）水平，以研究多形核细胞浸润和脂质过氧化反应。TNF-α R1基因缺失和英夫利西单抗给药可防止尿素、肌酐、γ GT、肾脏AST水平、iNOS和考克斯-2表达、NF-κ B易位、MPO活性和MDA水平的升高。TNF-α R1基因缺失和英夫利西单抗给药降低了与I/R相关的肾损伤的组织学证据，并导致硝基酪氨酸减少，表明亚硝化应激减少。我们的研究结果表明，TNF-α在I/R损伤中起着重要作用，并提出了一个假设，即TNF-α表达的调制可能代表一种新的和可能的策略。(C)2012爱思唯尔有限公司版权所有。
The role of the tumor necrosis factor (TNF)-alpha in the pathophysiology of renal ischemia/reperfusion (I/R) injury is unclear. We investigate the effects of TNF-alpha R1 gene deletion and infliximab administration on the degree of renal injury induced by I/R. TNF-alpha R1 knockout (TNF-alpha R1KO) and wild-type (TNF-alpha WT) mice were subjected to bilateral renal artery occlusion (30 min) and reperfusion (24 h). Infliximab (10 mg/kg subcutaneously, s.c.) was administered 1 h before ischemia. At the end of experiments, urea, creatinine, gamma GT, and AST were measured to assess renal function and reperfusion injury. Markers of oxidative stress, pro-inflammatory mediators, iNOS, COX-2, and NF-kappa B signaling pathway were measured. Kidney myeloperoxidase (MPO) activity and malondialdehyde (MDA) levels were measured to study polymorphonuclear cell infiltration and lipid peroxidation. TNF-alpha R1 gene deletion and infliximab administration prevented the increase of urea, creatinine, gamma GT, kidney AST levels, iNOS and COX-2 expression, NF-kappa B translocation, MPO activity and MDA levels. TNF-alpha R1 gene deletion and infliximab administration lowered the histological evidence of renal damage associated with I/R and caused a reduction of nitrotyrosine suggesting reduced nitrosative stress. Our results demonstrate that TNF-alpha plays an important role in I/R injury and put forward the hypothesis that modulation of TNF-alpha expression may represent a novel and possible strategy. (C) 2012 Elsevier B.V. All rights reserved.