缺氧诱导因子-2α通过限制NKT细胞毒性来保护肾脏缺血再灌注损伤

发布时间：2018-01-08 09:09

本文关键词：缺氧诱导因子-2α通过限制NKT细胞毒性来保护肾脏缺血再灌注损伤　出处：《上海交通大学》2015年硕士论文　论文类型：学位论文

【摘要】：急性肾损伤(Acute kidney injury,AKI)是肝移植术后常见的并发症,术中肾脏缺血再灌注损伤(ischemia/reperfusion injury,IRI)是导致肝移植术后AKI发生的主要原因之一。在肾脏缺血再灌注损伤中,CD4阳性自然杀伤T细胞是主要的早期起作用的细胞类型并且发挥着基本的免疫调节作用。因为在病理生理条件下淋巴细胞处于不同的氧分压环境中,我们假设缺氧诱导因子HIF在NKT细胞激活过程中起作用并决定肾脏缺血再灌注的最终结果。我们使用Lck-Cre转基因小鼠来干扰T细胞和NKT细胞中的HIF-2α基因,并且发现HIF-2α敲除可以使外周NKT细胞表面的Fas配体表达上调,但是对传统的T细胞表面Fas配体表达无影响。HIF-2α基因敲除可以促使NKT细胞向缺血的肾脏浸润并加重肾脏缺血再灌注损伤,体内敲除NKT1.1细胞或者Fas配体阻断可以抵消这个结果。和野生型小鼠的NKT细胞相比较,从HIF-2α敲除小鼠体内提取的NKT细胞过继转移给Rag1敲除小鼠后能引起严重的肾脏缺血再灌注损伤,并且损伤不能被腺苷受体A2A激动剂CGS21680保护。从经验上讲,缺氧诱导的NKT细胞表面表达的腺苷受体A2A以及因腺苷受体A2A激活而诱导的细胞内cAMP的产生都是HIF-2α依赖性的。野生型小鼠的胸腺NKT细胞提取后,先经CGS21680处理,再用过氧化氢刺激,野生型小鼠的胸腺NKT细胞表面Fas配体表达严重下降,而经过同样处理的HIF-2α敲除小鼠的NKT细胞则不存在这个效应。最后,我们发现CGS21680和脂多糖(内质网HIF2a诱导剂)能够协同地使肾脏缺血再灌注损伤减轻到惊人的程度,但是这种效果不存在于Mx1-Cre诱导的HIF-2α全身敲除小鼠上。总之,我们的结果揭示了以前从未被认知的缺氧/HIF-2α/腺苷2a信号通路轴,当面对氧化应激时,这条通路可以限制NKT的激活从而保护肾脏缺血再灌注损伤。
[Abstract]:Acute kidney injury (Acute kidney, injury, AKI) is a common complication after liver transplantation, renal ischemia reperfusion injury during operation (ischemia/reperfusion injury IRI) is a major cause of AKI after liver transplantation. After renal ischemia reperfusion injury, CD4 positive natural killer T cells are the main early role of cell types and plays a fundamental role in immune regulation. Because in pathophysiological conditions of lymphocytes at different oxygen partial pressure in the environment, we hypothesized that hypoxia inducible factor HIF activation plays a role and finally depends on the results of renal ischemia reperfusion in NKT cells. We used Lck-Cre transgenic mice to HIF-2 gene interference T cells and NKT cells, and found that HIF-2 alpha knockout can make peripheral Fas ligand NKT cell surface expression, but the traditional T cell surface expression of Fas ligand free Effect of.HIF-2 gene knockout can induce NKT cells to the ischemic kidney infiltration and aggravate renal ischemia-reperfusion injury in vivo knockdown NKT1.1 cells or Fas ligand blocking can offset the results. And wild type mice NKT cells compared to knockout mice NKT cell adoptive transfer to the Rag1 knockout mice can cause severe renal ischemia reperfusion injury from HIF-2 alpha, and the injury could not be A2A adenosine receptor agonist CGS21680 protection. Speaking from experience, NKT cell surface expression of hypoxia induced by adenosine receptor A2A and A2A adenosine receptor activation induced by intracellular cAMP generation is HIF-2 alpha dependent wild. Type of thymus NKT cells after extraction by CGS21680 treatment, and hydrogen peroxide stimulation, thymus NKT cell surface expression of Fas ligand in wild-type mice declined seriously, and after the same treatment HIF-2 Alpha knockout mice NKT cells did not have this effect. Finally, we found that CGS21680 and lipopolysaccharide (ER HIF2a inducer) can collaborate to make renal ischemia reperfusion injury reduced to an astonishing degree, but this effect does not exist in the Mx1-Cre induced systemic HIF-2 alpha knockout mice. In conclusion, our results reveals never before known hypoxia /HIF-2 alpha / adenosine 2A signaling axis, when faced with oxidative stress, this pathway can be activated to protect the renal ischemia reperfusion injury NKT.

【学位授予单位】：上海交通大学
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：R692

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