Elevation of ISG15 promotes diabetic kidney disease by modulating renal tubular epithelial cell pyroptosis

IF 7.9 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Clinical and Translational Medicine Pub Date : 2025-06-03 DOI:10.1002/ctm2.70337

Lingzhi Huang, Xinyi Chen, Yawen Shao, Shujun Deng, Chen Wang, Jianqiao Chen, Yongsheng Xie, Siming Yuan, Liqin Tang

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Abstract

Background

Fibrosis and inflammation in the renal tubular epithelial cells (TECs) are key contributors to the pathology of diabetic kidney disease (DKD). Nevertheless, the precise triggers of these processes remain unclear. This study aimed to explore the role of interferon-stimulated gene 15 (ISG15) in the injury of TECs induced by high glucose (HG) conditions and its implications for the development of DKD.

Methods

ISG15 knockout (ISG15 KO) mice injected with streptozotocin-treated mice on a high-fat diet were used to investigate its role in DKD. Cellular models with ISG15 knockdown were exposed to HG conditions to assess the effects of ISG15 on cellular responses. Subsequently, we evaluated the impact of ISG15 on pyroptosis, a form of programmed cell death, to understand its potential role in DKD pathology. Furthermore, RNA sequencing (RNA-seq) and molecular biology techniques were employed to explore the signalling pathways potentially regulated by ISG15.

Results

We first confirmed an up-regulation of ISG15 within the renal tubule in DKD. The deletion of ISG15 alleviated renal functional damage, fibrosis and inflammation, which correlated with reduced ISGylation levels. Mechanistic investigation revealed that HG stimulation in TECs disrupted the mtDNA–cGAS–STING signalling, which exacerbates the DKD through the NLRP3–CASP1–GSDMD axis. Furthermore, we uncovered a bidirectional regulatory loop between STING and ISG15, with STING enhancing ISG15 expression upstream and ISG15 modulating STING expression through ISGylation.

Conclusion

ISG15–mtDNA–STING emerges as a critical hub that integrates the processes of pyroptosis, fibrosis and inflammation. Therapeutic interventions that target this signalling network at various levels may pave the way for innovative treatments for DKD.

Key points

ISG15 is highly expressed in both DKD mice and renal tubular epithelial cell cultured in HG condition.
ISG15 promotes DKD pyroptosis via NLRP3–CASP1–GSDMD axis.
ISG15–mtDNA–STING emerges as a critical hub that integrates the processes of pyroptosis.

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ISG15的升高通过调节肾小管上皮细胞焦亡促进糖尿病肾病

肾小管上皮细胞（tec）的纤维化和炎症是糖尿病肾病（DKD）病理的关键因素。然而，这些过程的确切触发因素仍不清楚。本研究旨在探讨干扰素刺激基因15 （ISG15）在高糖（HG）诱导的tec损伤中的作用及其对DKD发展的影响。方法采用ISG15基因敲除（ISG15 KO）小鼠注射链脲佐菌素处理小鼠高脂饮食，研究其在DKD中的作用。将ISG15敲低的细胞模型暴露在HG条件下，以评估ISG15对细胞反应的影响。随后，我们评估了ISG15对焦亡（程序性细胞死亡的一种形式）的影响，以了解其在DKD病理中的潜在作用。此外，利用RNA测序（RNA-seq）和分子生物学技术探索ISG15可能调控的信号通路。我们首先证实了肾小管中ISG15的上调。ISG15的缺失减轻了肾功能损害、纤维化和炎症，这与isg酰化水平的降低有关。机制研究表明，HG刺激TECs破坏mtDNA-cGAS-STING信号通路，通过NLRP3-CASP1-GSDMD轴加重DKD。此外，我们发现STING和ISG15之间存在一个双向调控环，STING在上游增强ISG15的表达，而ISG15则通过isg酰化调节STING的表达。结论ISG15-mtDNA-STING是整合焦亡、纤维化和炎症过程的关键枢纽。针对不同水平的信号网络的治疗干预可能为DKD的创新治疗铺平道路。ISG15在DKD小鼠和HG条件下培养的肾小管上皮细胞中均高表达。ISG15通过NLRP3-CASP1-GSDMD轴促进DKD焦亡。ISG15-mtDNA-STING是整合焦亡过程的关键枢纽。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Clinical and Translational Medicine Multiple-

CiteScore

15.90

自引率

1.90%

发文量

450

审稿时长

4 weeks

期刊介绍： Clinical and Translational Medicine (CTM) is an international, peer-reviewed, open-access journal dedicated to accelerating the translation of preclinical research into clinical applications and fostering communication between basic and clinical scientists. It highlights the clinical potential and application of various fields including biotechnologies, biomaterials, bioengineering, biomarkers, molecular medicine, omics science, bioinformatics, immunology, molecular imaging, drug discovery, regulation, and health policy. With a focus on the bench-to-bedside approach, CTM prioritizes studies and clinical observations that generate hypotheses relevant to patients and diseases, guiding investigations in cellular and molecular medicine. The journal encourages submissions from clinicians, researchers, policymakers, and industry professionals.