ACM Advances in Clinical Medicine 2161-8712 Scientific Research Publishing 10.12677/acm.2024.143929 ACM-83740 acm2024143_2731579405.pdf 医药卫生 补体因子H相关蛋白1在足细胞疾病中的研究进展 Research Progress of Complement Factor H-Related Protein 1 in Podocyte Diseases 欧 云塔娜 2 1 张 蕾 2 1 迪 丽努尔·图尔荪托合提 2 1 周 洪 2 1 张 莉 2 1 新疆医科大学第五附属医学院肾病科，新疆 乌鲁木齐 null 07 03 2024 14 03 1956 1960 © Copyright 2014 by authors and Scientific Research Publishing Inc. 2014 This work is licensed under the Creative Commons Attribution International License (CC BY). http://creativecommons.org/licenses/by/4.0/

足细胞疾病(podocytopathies)是指直接或间接的足细胞损伤导致蛋白尿的肾脏疾病。国内外许多学者发现补体系统与足细胞损伤相关，补体因子H (complement factor H, CFH)及补体因子H相关蛋白1 (complement factor H-related 1, CFHR1)是补体替代途径激活过程中起重要调节作用的血浆蛋白。CFHR1在足细胞疾病中的发病机制至今仍不清楚，目前研究发现补体替代途径所介导的炎症反应可能起到关键作用，而CFHR1是补体替代途径激活过程中重要的调节物质。本文对CFHR1在足细胞疾病中的作用进行综述，以期为相关足细胞疾疾病的诊断和治疗提供参考。 Podocytopathies refer to kidney diseases that lead to proteinuria due to direct or indirect podocyte injury. Many scholars at home and abroad have found that the complement system is related to podocyte injury, and complement factor H (CFH) and complement factor H-related protein 1 (CFHR1) are plasma proteins that play an important regulatory role in the activation of the complement alternative pathway. The pathogenesis of CFHR1 in podocytopathies is still unclear. Current research has found that the inflammatory response mediated by the complement alternative pathway may play a key role, and CFHR1 is an important regulatory substance in the activation process of the complement alternative pathway. This article summarizes the role of CFHR1 in podocytopathies, aiming to provide reference value for the diagnosis and treatment of related podocyte diseases.

 补体因子H相关蛋白，补体系统，足细胞疾病, Complement Factor H-Related Protein Complement System Podocytopathies 摘要

足细胞疾病(podocytopathies)是指直接或间接的足细胞损伤导致蛋白尿的肾脏疾病。国内外许多学者发现补体系统与足细胞损伤相关，补体因子H (complement factor H, CFH)及补体因子H相关蛋白1 (complement factor H-related 1, CFHR1)是补体替代途径激活过程中起重要调节作用的血浆蛋白。CFHR1在足细胞疾病中的发病机制至今仍不清楚，目前研究发现补体替代途径所介导的炎症反应可能起到关键作用，而CFHR1是补体替代途径激活过程中重要的调节物质。本文对CFHR1在足细胞疾病中的作用进行综述，以期为相关足细胞疾疾病的诊断和治疗提供参考。

 关键词

补体因子H相关蛋白，补体系统，足细胞疾病

 Research Progress of Complement Factor H-Related Protein 1 in Podocyte Diseases<sup> </sup>

Ou∙Yuntana, Lei Zhang, Dilinuer∙Tursun Tuoheti, Hong Zhou, Li Zhang

Department of Nephrology, The Fifth Affiliated Hospital of Xinjiang Medical University, Urumqi Xinjiang

Received: Feb. 27th, 2024; accepted: Mar. 22nd, 2024; published: Mar. 29th, 2024

 ABSTRACT

Podocytopathies refer to kidney diseases that lead to proteinuria due to direct or indirect podocyte injury. Many scholars at home and abroad have found that the complement system is related to podocyte injury, and complement factor H (CFH) and complement factor H-related protein 1 (CFHR1) are plasma proteins that play an important regulatory role in the activation of the complement alternative pathway. The pathogenesis of CFHR1 in podocytopathies is still unclear. Current research has found that the inflammatory response mediated by the complement alternative pathway may play a key role, and CFHR1 is an important regulatory substance in the activation process of the complement alternative pathway. This article summarizes the role of CFHR1 in podocytopathies, aiming to provide reference value for the diagnosis and treatment of related podocyte diseases.

Keywords:Complement Factor H-Related Protein, Complement System, Podocytopathies

Copyright © 2024 by author(s) and beplay安卓登录

This work is licensed under the Creative Commons Attribution International License (CC BY 4.0).

http://creativecommons.org/licenses/by/4.0/

 1. 引言

足细胞疾病(podocytopathies)是指直接或间接的足细胞损伤导致蛋白尿的肾脏疾病，主要包括局灶节段硬化性肾小球症(focal segmental glomerular sclerosis, FSGS)，膜性肾病，微小病变，糖尿病肾病及狼疮性肾炎等疾病 [ 1 ] 。

国外学者(孟德尔等)及国内学者(李卫国等)等多位学者认定，足细胞损伤后，早期出现足突融合，后期病情进展，足细胞数量和密度大幅减少后，肾小球滤过屏障破坏后造成大量蛋白尿 [ 2 ] [ 3 ] [ 4 ] 。国内外许多学者发现补体系统与足细胞损伤相关。补体系统是先天免疫的重要组成部分，参与人体免疫调节及免疫损伤性反应。补体系统由20多种非特异性免疫球蛋白组成，其激活途径主要有经典途径、替代途径和凝集素途径 [ 5 ] 。其中补体因子H受到较多国内外学者关注。

 2. 补体因子H的组成和功能

补体因子H (以前称为β1H)是一种丰富的血清糖蛋白，在肝脏中结构性表达，也可由多种细胞类型局部表达，包括视网膜色素上皮细胞、内皮细胞、上皮细胞、血小板和间充质干细胞等。血清H因子浓度约为500 μg/ml，但因遗传和环境因素不同，其变化范围可能在116~562 μg/ml之间。因子H加速了替代途径C3转换酶(C3b, BB)的衰退，也是因子I介导的C3b裂解和失活的辅助因子 [ 6 ] 。

补体因子H (complement factor H, CFH)及补体因子H相关蛋白1 (complement factor H related 1, CFHRI)是补体替代途径激活过程中起重要调节作用的血浆蛋白。其中CFH在补体活化过程中发挥抑制作用，而CFHRI则通过竞争性结合CFH表面配体影响CFH的抑制功能 [ 7 ] 。CFHR1是补体因子H相关蛋白家族中的一种蛋白质，其单基因片段位于人类染色体1q32上的一个独特基因簇区段内 [ 8 ] 。当补体系统被激活时会产生不稳定的蛋白酶复合物，即C3转化酶和C5转化酶。CFHRI作为补体调节物质，通过控制C3转化酶和C5转化酶的生成和活性，决定Cab和C5b的作用途径和功能 [ 9 ] 。Kerjaschki等人在Heyman肾炎模型中研究发现，补体系统的激活以及补体终末产物C5b-9的形成，是导致足细胞损伤和蛋白尿形成重要因素 [ 10 ] [ 11 ] [ 12 ] 。本文对CFHＲ1在各类足细胞疾病中的作用进行综述，以期对相关足细胞疾病的诊断和治疗的参考价值。

 3. 补体因子H相关蛋白1与足细胞疾病的关联 3.1. 非典型性溶血性尿毒综合征

非典型性溶血性尿毒综合征(atypical, non-diarrhea-associated hemolytic uremic syndrome, a HUS) a HUS是一种罕见的由于血小板在肾脏的微循环中形成血栓而引起的一种临床综合征，常发生于儿童和青壮年，其特征为微血管内溶血、血小板减少和急性肾损伤。研究证实CFH和CFHR1基因杂合突变、CFHR1基因缺失与a HUS的发病机制有关 [ 13 ] 。2009年Dragon-Durey等人研究发现，CFHR1缺失是非典型溶血尿毒综合征的易感因素 [ 14 ] 。2013年Eyler等人发现一位非典型溶血尿毒综合征患者体内存在CFHR1/CFH融合基因 [ 15 ] 。对于a HUS患者，由于CFH基因突变或缺失，使得血清中CFH水平低下或生理功能缺失，因而无法有效抑制补体替代途径的激活，造成肾小球基底膜和内皮层细胞损害 [ 16 ] 。

 3.2. 原发性膜性肾病(IMN)

最近，人们通过对原发性膜性肾病(IMN)的深入研究，进一步明确了补体激活，活化终末产物C5b-9的产生在足细胞损伤和肾小球疾病发生中的关键作用 [ 17 ] [ 18 ] [ 19 ] 。

特发性膜性肾病(IMN)是原发性成人肾病综合征的常见病因之一，约占我国成人肾病综合征患者总数的25%左右，且近年发病率有持续升高趋势 [ 15 ] 。IMN的致病机制仍不十分明确，补体系统的过度激活导致足细胞损伤被认为是发病机制的关键环节 [ 20 ] 。在补体系统已知的三种激活途径中，凝集素途径和旁路途经被认为与IMN的发病机制相关。补体H因子(FH)为补体系统旁路途经的主要负向调控因子，可以通过多种方式减弱旁路途经的激活过程。Lindsay等人研究发现，足细胞来源的VEGF可以诱导足细胞表达补体H因子，表达的H因子对补体旁路激活有一定的抑制作用 [ 21 ] 。同时补体H因子也具有自身的调节因子：补体H因子相关蛋白1~5，这一类蛋白可以与补体H因子的表面受体竞争性结合，从而干扰H因子对旁路途经的抑制功能，间接调控补体旁路途经的活化 [ 22 ] 。

 3.3. IgA肾病

Ig A肾病(Ig A nephropathy, Ig AN) Ig AN是指肾小球系膜区以IgA或IgA沉积为主，伴或不伴有其他免疫球蛋白在肾小球系膜区沉积的原发性肾小球病 [ 23 ] [ 24 ] 。其临床表现为反复发作性肉眼血尿或镜下血尿，可伴有不同程度蛋白尿，部分患者可以出现严重高血压或者肾功能不全。是我国乃至全球最常见的原发性肾小球肾炎，也是引起终末期肾脏病的重要原因之一。目前被广泛认为是一种多基因疾病，其发病机制仍不明确，但Ig AN患者的一个重要特征是存在肾小球循环免疫复合物，其由缺乏半乳糖的Ig A1、铰链区异常O-糖基化的Ig G自身抗体和C3组成 [ 25 ] 。大量研究已经证实，在已知的3种补体激活途径中，补体替代途径和凝集素途径在Ig AN的发病机制中发挥重要作用，补体活化是Ig AN发生及发展的重要机制 [ 26 ] 。Gharavi等人对欧洲裔的IgA肾病患者进行了全基因组关联性分析，研究发现CFHR1/CFHR3基因缺失对IgA肾病的发生是保护因素 [ 27 ] 。但是目前关于如何诱导补体替代途径激活的机制尚未完全清楚，有待我们进一步发现。

 4. 展望

足细胞疾病的发展为足细胞损伤，产生蛋白尿，最后发展为肾小球硬化。明确补体系统与足细胞损伤的关系，掌握足细胞损伤的机制，早期针对性治疗，将成为肾脏病患者的福音。明确诱导足细胞损伤的补体及相关蛋白等，可能会为肾脏疾病带来新的治疗靶点。对足细胞损伤机制深入研究以及阐明足细胞病变在肾小球疾病发生、发展中的作用，将为肾小球疾病的防治拓展广阔的前景。

 文章引用

欧云塔娜,张 蕾,迪丽努尔·图尔荪托合提,周 洪,张 莉. 补体因子H相关蛋白1在足细胞疾病中的研究进展Research Progress of Complement Factor H-Related Protein 1 in Podocyte Diseases[J]. 临床医学进展, 2024, 14(03): 1956-1960. https://doi.org/10.12677/acm.2024.143929

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