转化生长因子-β与肾脏纤维化的研究进展
孟晓明¹, 蓝辉耀^2,*
1安徽医科大学药学院；抗炎免疫药物教育部重点实验室；重大自身免疫性疾病安徽省重点实验室，合肥 230032；²香港中文大学医学院内科及药物治疗系，香港；香港中文大学深圳研究院，深圳 518172
摘要
转化生长因子-β (transforming growth factor-β, TGF-β)是促进肾脏纤维化、促进慢性肾脏疾病进展，甚至进入终末期肾脏疾病的重要因子之一。TGF-β可通过激活下游Smad依赖或非依赖途径诱导胶原等细胞外基质的合成，并抑制胶原的降解。疾病状态下大量分泌的TGF-β1还可促进肾小管上皮细胞、内皮细胞、足细胞、巨噬细胞、成纤维细胞、周细胞等细胞的凋亡、增殖及纤维化反应，并诱导肌纤维母细胞的生成、激活与增殖。TGF-β通过与BMP-7、Wnt/β-catenin、MAPK等经典通路相互调控，共同介导了肾纤维化的发生和发展。Smad3被认为是TGF-β通路下游最关键的致纤维化分子，其相关的表观遗传学修饰(如非编码RNA、DNA和组蛋白的表观修饰等)是近来研究的热点。尽管TGF-β功能多样、作用机制复杂，导致靶向TGF-β的抗肾脏纤维化临床治疗难以获得理想效果，TGF-β下游相关靶点的寻找仍被视为重要的肾脏纤维化防治策略。
关键词： 肾脏纤维化; TGF-β/Smads; 表观遗传学修饰; 肌纤维母细胞; 巨噬细胞
分类号：R334+.1;Q491

Transforming growth factor-β and renal fibrosis
MENG Xiao-Ming¹, LAN Hui-Yao^2,*
1School of Pharmacy, Anhui Medical University; Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education; The Key Laboratory of Major Autoimmune Diseases, Hefei 230032, China；²Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China; Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen 518172, China
Abstract
Transforming growth factor-β (TGF-β) is a driving force of renal fibrosis, which may lead to chronic kidney diseases and even end stage renal diseases. By activating canonical and non-canonical signaling pathways, TGF-β promotes the synthesis of extracellular matrix while preventing their degradation. In the injured kidney, TGF-β induces apoptosis, proliferation and fibrotic response of renal cells including epithelial cells, endothelial cells, podocytes, fibroblasts, pericytes and macrophages, and it also promotes transdifferentiation, activation and proliferation of myofibroblasts. Additionally, TGF-β exerts profibrotic effects by interplaying with other signaling pathways like BMP-7, Wnt/β-catenin and MAP kinase. Smad3 is the central pathological gene in renal fibrosis, and epigenetic regulation of TGF-β/Smad3 is a hot topic in kidney field. Although direct targeting TGF-β may cause side effects including tumorigenesis and immune diseases, the therapeutic strategies targeting the balance of downstream Smad3 and Smad7 may prevent or delay the progression of fibrotic kidney disease.


Key words: renal fibrosis; TGF-β/Smads; epigenetic modifications; myofibroblast; Macrophage

收稿日期：2018-06-05　　录用日期：2018-09-21
通讯作者：蓝辉耀　　E-mail: hylan@cuhk.edu.hk
DOI: 10.13294/j.aps.2018.0085
引用本文：
孟晓明, 蓝辉耀. 转化生长因子-β与肾脏纤维化的研究进展[J]. 生理学报 2018; 70 (6): 612-622.
MENG Xiao-Ming, LAN Hui-Yao. Transforming growth factor-β and renal fibrosis. Acta Physiol Sin 2018; 70 (6): 612-622 (in Chinese with English abstract).



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