PAD4促进巨噬细胞迁移，加重糖尿病肾病小管间质损伤。

IF 12 1区医学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Molecular Therapy Pub Date : 2025-10-06 DOI:10.1016/j.ymthe.2025.10.009

Yunjie Xiong,Ruolin Li,Xiangjun Chen,Chuan Peng,Qinglian Zeng,Shuangshuang Zhu,Furong He,Jinshan Wu,Jiangyun Lei,Miaoyun Chen,Shiyun Tong,Yue Sun,Yong Xu,Wei Huang,Shumin Yang,Qifu Li,Jinbo Hu,Linqiang Ma

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引用次数: 0

摘要

肽基精氨酸脱亚胺酶4 （PAD4）是一种主要在髓细胞中表达的酶，其在糖尿病肾病（DKD）中的作用尚不清楚。我们对来自UK Biobank的469,779名参与者中发现的48种PADI4变异进行了功能表征，并检查了它们与肾功能的关系。我们发现大多数PADI4变异导致功能丧失，这与较高的肾小球滤过率显著相关。我们在DKD患者和DKD动物模型中观察到肾小管间质中PAD4的表达增强。巨噬细胞PAD4缺乏和PAD4抑制剂GSK484均可通过减少糖尿病小鼠模型巨噬细胞浸润而显著减轻肾小管间质损伤。在机制上，PAD4与p65相互作用，促进其与Cmklr1启动子的结合，诱导Cmklr1的表达，从而增强巨噬细胞的迁移。这些发现证明了pad4介导的巨噬细胞迁移在DKD小管间质损伤中的关键作用。

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PAD4 promotes macrophage migration to aggravate tubulointerstitial injury in diabetic kidney disease.

Peptidyl Arginine Deiminase 4 (PAD4) is an enzyme predominantly expressed in myeloid cells, and its role in diabetic kidney disease (DKD) remains unknown. We functionally characterized 48 PADI4 variants identified among 469,779 participants from UK Biobank and examined their associations with renal function. We found that most PADI4 variants causes loss of function, which was significantly associated with higher estimated glomerular filtration rate. We observed an enhanced PAD4 expression in renal tubulointerstitium among DKD patients and animal models of DKD. Both PAD4 deficiency in macrophages and PAD4 inhibitor GSK484 significantly alleviated renal tubulointerstitial injury by reducing macrophage infiltration in diabetic mice models. Mechanistically, PAD4 interacted with p65 to promote its binding to Cmklr1 promoter and induce the expression of Cmklr1, which led to an enhanced macrophage migration. These findings demonstrate the crucial role of PAD4-mediated macrophage migration in tubulointerstitial injury of DKD.

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来源期刊

Molecular Therapy 医学-生物工程与应用微生物

CiteScore

19.20

自引率

3.20%

发文量

357

审稿时长

3 months

期刊介绍： Molecular Therapy is the leading journal for research in gene transfer, vector development, stem cell manipulation, and therapeutic interventions. It covers a broad spectrum of topics including genetic and acquired disease correction, vaccine development, pre-clinical validation, safety/efficacy studies, and clinical trials. With a focus on advancing genetics, medicine, and biotechnology, Molecular Therapy publishes peer-reviewed research, reviews, and commentaries to showcase the latest advancements in the field. With an impressive impact factor of 12.4 in 2022, it continues to attract top-tier contributions.