NLRX1调控的线粒体复苏在移植肾缺血再灌注损伤修复中的作用及其分子机制

缺血再灌注损伤（IRI）对移植肾状态和受体长期存活有重要影响，线粒体功能障碍是主要致病因素，而损伤后修复过程中线粒体复苏的机制尚不明晰。我们发现：人移植肾零点穿刺标本中NLRX1的表达量与缺血时间长短有关，小鼠体内及体外肾IRI实验证实NLRX1通过影响线粒体的功能减轻急性肾小管损伤的发生，而NLRX1在损伤后修复期表达量明显增加，且与线粒体呼吸链复合物活性、胞内ATP含量及线粒体调节因子SIRT3活化呈正相关。故提出假说：NLRX1正向调控损伤后的线粒体功能复苏、增加ATP合成、促进细胞增殖在移植肾IRI修复中发挥保护作用。本研究拟采用基因敲除小鼠肾移植模型，通过转录组测序、液相芯片等现代分子生物学技术及相关体外细胞生物学实验，明确NLRX1在肾IRI修复过程中的作用途径，揭示影响线粒体功能调控和肾损伤修复的分子机制，为固有免疫系统在肾脏IRI的防治提供新的治疗靶点及实验依据。

Ischemia-reperfusion injury (IRI) plays an important role in the state of transplanted kidney and the long-term survival of recipients. Mitochondrial dysfunction is the main pathogenic factor, but the mechanism of mitochondrial resuscitation in the process of repair after injury is not clear. We found that the expression of NLRX1 was related to the duration of ischemia. IRI experiments in vivo and in vitro showed that the expression of NLRX1 decreased the occurrence of acute renal tubular injury by affecting the function of mitochondria, and the expression of NLRX1 increased significantly in the repair period after injury, and was positively related to the activity of mitochondrial respiratory chain complex, the content of intracellular ATP and the activity of mitochondrial regulatory factor SIRT3. It is suggested that NLRX1 may play a protective role in transplant renal IRI repair by regulating mitochondrial function recovery, increasing ATP synthesis and promoting cell proliferation. In this study, we intend to use the gene knockout mouse renal transplantation model, through the transcriptome sequencing, liquid-phase chip and other modern molecular biological technologies and related in vitro cell biology experiments, to clarify the specific role of NLRX1 in the process of renal IRI repair and reveal the molecular mechanism affecting the regulation of mitochondrial function and the repair of renal injury. It will provide a new treatment and experimental basis for the prevention and treatment of renal IRI through innate immune system.