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RNF125介导的RIG-I泛素化降解减少促进肾脏炎症和纤维化进展

李露新¹, 姬婷婷¹, 陆丽², 李肖瑛¹, 陆利民², 白寿军^1,*

¹复旦大学附属中山医院青浦分院肾内科，上海 201700；²复旦大学基础医学院生理与病理生理学系，上海 200032

摘要

持续的炎症反应是肾脏纤维化发生和进展的关键因素。模式识别受体维甲酸诱导基因I (retinoic acid-inducible gene-I, RIG-I)激活引起的炎症因子生成参与肾脏纤维化进展，本研究旨在探讨调控RIG-I的上游机制。选用8周龄雄性C57BL/6小鼠，用单侧输尿管梗阻(unilateral ureteral obstruction, UUO)建立肾纤维化模型，14天后收集组织样本进行分析。离体实验在转化生长因子β (transforming growth factor-β, TGF-β)刺激的小鼠肾小管上皮细胞中进行。结果显示，与对照组相比，UUO小鼠肾脏出现明显的纤维化改变，RIG-I、磷酸化NF-κB p65和炎症因子水平升高，同时E3泛素连接酶RNF125的蛋白水平明显下调，并且主要定位在肾小管上皮细胞；在离体培养的肾小管上皮细胞中给予TGF-β刺激同样引起RIG-I、磷酸化NF-κB p65和炎症因子水平升高，并伴有RNF125水平下降；RIG-I能够发生泛素化修饰，免疫共沉淀结果验证了RNF125与RIG-I存在直接相互作用，且过表达RNF125能够促进RIG-I的泛素化，加速RIG-I通过泛素蛋白酶体途径降解。在肾组织和离体肾小管上皮细胞中过表达RNF125可以有效缓解炎症反应和肾脏纤维化。综上所述，本研究结果证实，在病理情况下RNF125水平下降，导致RIG-I的泛素化降解减少，下游NF-κB信号通路激活，炎症因子产生增加，最终促进肾脏纤维化的进展。

关键词： 肾纤维化; 炎症; 泛素化; RNF125; RIG-I

Reductionin RNF125-mediated RIG-I ubiquitination and degradation promotes renal inflammation and fibrosis progression

LI Lu-Xin¹, JI Ting-Ting¹, LU Li², LI Xiao-Ying¹, LU Li-Min², BAI Shou-Jun^1,*

¹Department of Nephrology, Qingpu Branch of Zhongshan Hospital Affiliated to Fudan University, Shanghai 201700, China；²Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China

Abstract

Persistent inflammation plays a pivotal role in the initiation and progression of renal fibrosis. Activation of the pattern recognition receptor retinoic acid-inducible gene-I (RIG-I) is implicated in the initiation of inflammation. This study aimed to investigate the upstream mechanisms that regulates the activation of RIG-I and its downstream signaling pathway. Eight-week-old male C57BL/6 mice were used to establish unilateral ureteral obstruction (UUO)-induced renal fibrosis model, and the renal tissue samples were collected 14 days later for analysis. Transforming growth factor-β (TGF-β)-treated mouse renal tubular epithelial cells were used in in vitro studies. The results demonstrated that, compared to the control group, UUO kidney exhibited significant fibrosis, which was accompanied by the increases of RIG-I, p-NF-κB p65 and inflammatory cytokines, such as TNF-α and IL-1β. Additionally, the protein level of the E3 ubiquitin ligase RNF125 was significantly downregulated and predominantly localized in the renal tubular epithelial cells. Similarly, the treatment of tubular cells with TGF-β induced the increases in RIG-I, p-NF-κB p65 and inflammatory cytokines while decreasing RNF125. Co-immunoprecipitation (Co-IP) assays confirmed that RNF125 was able to interact with RIG-I. Overexpression of RNF125 promoted the ubiquitination of RIG-I, and accelerated its degradation via the ubiquitin-proteasome path way. Overexpression of RNF125 in UUO kidneys and in vitro tubular cells effectively mitigated the inflammatory response and renal fibrosis. In summary, our results demonstrated that the decrease in RNF125 under pathological conditions led to reduction in RIG-I ubiquitination and degradation, activation of the downstream NF-κB signaling pathway and increase in inflammatory cytokine production, which promoted the progression of renal fibrosis.

Key words: kidney fibrosis; inflammation; ubiquitination; RNF125; RIG-I

收稿日期：　　录用日期：

通讯作者：白寿军　　E-mail:

DOI: 10.13294/j.aps.2025.0028

引用本文：

李露新, 姬婷婷, 陆丽, 李肖瑛, 陆利民, 白寿军. RNF125介导的RIG-I泛素化降解减少促进肾脏炎症和纤维化进展[J]. 生理学报 2025; 77 (3): 385-394.

LI Lu-Xin, JI Ting-Ting, LU Li, LI Xiao-Ying, LU Li-Min, BAI Shou-Jun. Reductionin RNF125-mediated RIG-I ubiquitination and degradation promotes renal inflammation and fibrosis progression. Acta Physiol Sin 2025; 77 (3): 385-394 (in Chinese with English abstract).