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促红细胞生成素受体在缺血再灌注所致急性肾损伤和修复或纤维化中的作用及机制

韩成¹, 刘瑀¹, 吴圆圆², 杨斌^1,3,*

¹南通-莱斯特联合肾脏病学研究所，南通大学附属医院肾内科，南通 226001；²南通大学医学院病理系，南通 226001；³莱斯特大学生命科学院心血管科学系肾脏研究组，莱斯特大学医院，莱斯特 LE1 9HN，英国

摘要

急性肾损伤(acute kidney injury, AKI)为常见临床危重疾病，发病率及死亡率均较高，部分存活患者还会进展为慢性肾脏病。肾缺血再灌注(ischemia-reperfusion, IR)是AKI的主要病因之一，细胞凋亡、炎症和吞噬在IR所致AKI及其修复和潜在纤维化进展中起重要作用。促红细胞生成素(erythropoietin, EPO)的同源二聚受体[homodimer EPO receptor, (EPOR)2]及EPO受体与β共同受体(β common receptor, βcR)形成的异源二聚受体(EPOR/βcR)的表达在IR所致AKI的进展过程中发生动态变化，两者在AKI及修复早期协同参与保护作用，但在AKI晚期转归中则有不同的影响，前者促进肾脏纤维化，而后者则帮助肾脏修复及重建。目前对(EPOR)2和EPOR/βcR的作用机制、信号通路以及不同作用的拐点等仍不完全清楚。已有报道表明，EPO的3D结构中B螺旋表面肽(helix B surface peptide, HBSP)和环化的HBSP (cyclic HBSP, CHBP)仅与EPOR/βcR结合，研发合成HBSP推进了EPOR/βcR在AKI早期保护作用和机制的研究，更为区别后期(EPOR)2促进纤维化、而EPOR/βcR启动修复及重建的不同作用提供了有效的研究工具。本综述着重讨论(EPOR)2和EPOR/βcR在IR所致AKI、修复和纤维化过程中对细胞凋亡、炎症和吞噬的影响，并比较信号通路及转归机制的异同。

关键词： 急性肾损伤; 缺血再灌注损伤; 促红细胞生成素受体; 修复; 纤维化

Update on the role and mechanism of erythropoietin receptor in acute kidney injury and repair or fibrosis

HAN Cheng¹, LIU Yu¹, WU Yuan-Yuan², YANG Bin^1,3,*

¹Nantong-Leicester Joint Institute of Kidney Science, Department of Nephrology, Affiliated Hospital of Nantong University, Nantong 226001, China；²Department of Pathology, Medical School, Nantong University, Nantong 226001, China；³Renal Research Group, Cardiovascular Sciences, University of Leicester, University Hospitals of Leicester, Leicester, LE1 9HN, UK

Abstract

Acute kidney injury (AKI) is a common critical disease clinically with high morbility and mortality and some survival patients also progress to chronic kidney disease. Renal ischemia-reperfusion (IR) is one of the main causes of AKI, in which, its repair and potential fibrosis, apoptosis, inflammation and phagocytosis play important roles. During the progression of IR-induced AKI, the expression of erythropoietin homodimer receptor (EPOR)2 and EPOR and β common receptor formed heterodimer receptor (EPOR/βcR) is changed dynamically. Moreover, (EPOR)2 and EPOR/βcR may synergistically participate in renoprotection at the stage of AKI and early repair, whereas at the late stage of AKI, the (EPOR)2 induces renal fibrosis and the EPOR/βcR facilitates repair and remodelling. The underlying mechanism, signaling pathways and the different effect turning point of (EPOR)2 and EPOR/βcR have not been well defined. It has been reported that EPO, according to its 3D structure, derived helix B surface peptide (HBSP) and cyclic HBSP (CHBP) only bind to EPOR/βcR. Synthesized HBSP, therefore, provides an effective tool to distinguish the different roles and mechanisms of both receptors, with the (EPOR)2 promoting fibrosis or the EPOR/βcR leading to repair/remodelling at the late stage of AKI. This review discusses the similarities and differences of (EPOR)2 and EPOR/βcR in their impacts on apoptosis, inflammation and phagocytosis in AKI, repair and fibrosis post IR, associated mechanisms, signaling pathways and outcomes. 

Key words: acute kidney injury; ischemia-reperfusion injury; erythropoietin receptor; repair; fibrosis

收稿日期：　　录用日期：

通讯作者：杨斌　　E-mail:

DOI: 10.13294/j.aps.2023.0002

引用本文：

韩成, 刘瑀, 吴圆圆, 杨斌. 促红细胞生成素受体在缺血再灌注所致急性肾损伤和修复或纤维化中的作用及机制[J]. 生理学报 2023; 75 (1): 115-129.

HAN Cheng, LIU Yu, WU Yuan-Yuan, YANG Bin. Update on the role and mechanism of erythropoietin receptor in acute kidney injury and repair or fibrosis. Acta Physiol Sin 2023; 75 (1): 115-129 (in Chinese with English abstract).