内源性EPO通过mTOR介导的糖代谢重编程调控巨噬细胞极化在肾脏缺血再灌注损伤修复中的作用和机制

Kidney ischemia reperfusion injury (IRI) is inevitable during the procedure of kidney transplantation and influences the long-term outcome of renal allografts. The dynamic change of macrophage phenotype has been shown to play an important role in the pathophysiological process of kidney IRI. However, the underlying mechanism is still not fully understood. We previously found that erythropoietin (EPO) could facilitate the generation of M2 macrophage via its receptor-mediated pathways in vitro and antagonizing endogenous EPO signals decreases the M2/M1 macrophage ratio and delays the tissue repair in renal IRI mice model. Therefore, we hypothesize that endogenous EPO could regulate the macrophage polarization and consequently promote the kidney repair. In this respect, we will further explore the effect of EPO on the macrophage polarization and its molecular mechanism involving the EPO-mTOR-IRF4-mediated metabolic reprogramming through in vitro and in vivo experiments. Furthermore, macrophage-based novel therapeutic strategy for kidney IRI will also be developed. This project will further reveal the repair mechanism of kidney IRI and the regulation mechanism of macrophage polarization, providing novel ‘checkpoint’ and theoretical basis for clinical treatment of kidney IRI.

肾脏缺血再灌注损伤(IRI)是肾移植无法避免的问题，严重影响了移植肾的长期存活。巨噬细胞极化的动态变化在肾脏IRI过程中发挥了重要作用，但具体调控机制尚不完全明确。我们发现，促红细胞生成素(EPO)可以通过其受体介导的通路促进M2型巨噬细胞的生成，在小鼠肾脏IRI模型中阻断内源性EPO信号则可明显降低肾脏中M2型巨噬细胞的比例，并加重了肾损伤。因此，我们提出了“内源性EPO通过调控巨噬细胞极化参与肾脏损伤修复”这一科学假说，拟通过体内、外实验进一步研究内源性EPO促进肾脏巨噬细胞向M2型分化的规律，深入解析EPO-mTOR-IRF4信号轴介导的代谢变化调控巨噬细胞极化的分子机制，并探索以巨噬细胞调控为基础的肾脏IRI治疗新策略。本研究将进一步揭示肾脏损伤后的修复机制和肾脏微环境调控巨噬细胞极化的机理，为临床改善肾脏IRI治疗提供新思路和理论依据。

肾移植已经成为治疗终末期肾病最有效的方式，但是肾脏缺血再灌注损伤（IRI）仍是目前肾移植过程中无法避免的问题，严重影响移植肾的长期存活。研究表明，巨噬细胞的极化和功能状态在肾损伤的病理生理过程中发挥了重要作用，调控巨噬细胞极化的内在机制是目前研究的热点问题。本项目利用促红细胞生成素（EPO）受体拮抗剂干预小鼠IRI模型，发现小鼠血清肌酐、尿素氮水平明显升高，病理学检测提示肾脏结构损伤加重，炎症指标上升，而M2型巨噬细胞减少；在此实验条件下，通过药物清除巨噬细胞逆转了阻断内源性EPO信号的作用，提示内源性EPO信号通过调控巨噬细胞促进组织修复。在体外实验中，加入凋亡细胞或EPO均可诱导M2型巨噬细胞基因的表达，加入凋亡细胞同时阻断EPOR信号通路明显抑制相关基因表达，证实凋亡细胞可以刺激巨噬细胞自分泌EPO。EPO信号可以增强巨噬细胞氧化磷酸化水平，并调控巨噬细胞功能性重编程。EPO训练M2型巨噬细胞可以明显提高治疗肾脏IRI的效果。本项目阐明了内源性EPO调控巨噬细胞极化的作用和机制，为形成以巨噬细胞基础的肾脏IRI细胞治疗提供了理论基础和实验依据。

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