DNAJC6在急性肾损伤中的作用：通过pgc -1α-介导的线粒体稳态保护肾小管上皮细胞的新靶点

IF 3.5 3区生物学 Q3 CELL BIOLOGY

Experimental cell research Pub Date : 2025-07-15 DOI:10.1016/j.yexcr.2025.114682

Liyun Ma , Jialiang Hui , Guangting He , Zaisheng Qin

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引用次数: 0

摘要

背景：急性肾损伤（Acute kidney injury， AKI）是一种严重威胁患者生命健康的临床综合征。其发病机制复杂，缺乏有效的治疗策略。线粒体稳态破坏在AKI进展中起关键作用，但其确切的分子机制尚不清楚。本研究旨在探讨DNAJC6在AKI中的作用及其线粒体稳态调节的分子机制。方法：利用顺铂诱导小鼠AKI模型和人近端小管上皮细胞系HK-2，采用生物信息学分析、细胞转染、免疫组化染色、免疫荧光、TUNEL实验、线粒体功能检测等多种实验方法，探讨DNAJC6在AKI中的作用及其分子机制。结果：在顺铂诱导的AKI模型中，肾脏DNAJC6表达降低。DNAJC6过表达可显著减轻肾损伤，减少细胞凋亡，减轻炎症反应。机制研究表明，DNAJC6通过促进PGC-1α核易位调节线粒体稳态。具体来说，DNAJC6改善了线粒体呼吸功能，降低了线粒体氧化应激水平。此外，DNAJC6增强线粒体生物发生，抑制炎症因子表达。PGC-1α敲低后，DNAJC6的保护作用几乎完全消失，证实PGC-1α是一个关键的分子介质。结论：本研究阐明了DNAJC6在AKI中通过pgc -1α介导的线粒体稳态保护肾小管上皮细胞的分子机制。这些发现不仅为AKI的发病机制提供了新的视角，而且为制定潜在的治疗策略提供了重要的理论基础。DNAJC6成为AKI治疗的一个有希望的分子靶点。

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DNAJC6 in acute kidney injury: A novel target for protecting renal tubular epithelial cells through PGC-1α-mediated mitochondrial homeostasis

Background

Acute kidney injury (AKI) is a severe clinical syndrome that critically threatens patients' lives and health. It is characterized by complex pathogenesis and lacks effective therapeutic strategies. Mitochondrial homeostasis disruption plays a pivotal role in AKI progression, yet its precise molecular mechanisms remain unclear. This study aimed to investigate the role of DNAJC6 in AKI and its molecular mechanism of mitochondrial homeostasis regulation.

Methods

Utilizing cisplatin-induced mouse AKI models and human proximal tubular epithelial cell line HK-2, we employed multiple experimental approaches including bioinformatics analysis, cell transfection, immunohistochemical staining, immunofluorescence, TUNEL assay, and mitochondrial function detection to explore the role and molecular mechanisms of DNAJC6 in AKI.

Results

In cisplatin-induced AKI models, renal DNAJC6 expression decreased. DNAJC6 overexpression markedly alleviated kidney injury, reduced cell apoptosis, and attenuated inflammatory responses. Mechanistic investigations revealed that DNAJC6 regulated mitochondrial homeostasis by promoting PGC-1α nuclear translocation. Specifically, DNAJC6 improved mitochondrial respiratory function and reduced mitochondrial oxidative stress levels. Moreover, DNAJC6 enhanced mitochondrial biogenesis and suppressed inflammatory factor expression. Upon PGC-1α knockdown, DNAJC6's protective effects were almost completely abolished, confirming that PGC-1α was a critical molecular mediator.

Conclusion

This study elucidated the molecular mechanism by which DNAJC6 protected renal tubular epithelial cells through PGC-1α-mediated mitochondrial homeostasis in AKI. These findings not only provide a novel perspective on AKI pathogenesis but also offer a crucial theoretical foundation for developing potential therapeutic strategies. DNAJC6 emerges as a promising molecular target for AKI treatment.

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来源期刊

Experimental cell research 医学-细胞生物学

CiteScore

7.20

自引率

0.00%

发文量

295

审稿时长

30 days

期刊介绍： Our scope includes but is not limited to areas such as: Chromosome biology; Chromatin and epigenetics; DNA repair; Gene regulation; Nuclear import-export; RNA processing; Non-coding RNAs; Organelle biology; The cytoskeleton; Intracellular trafficking; Cell-cell and cell-matrix interactions; Cell motility and migration; Cell proliferation; Cellular differentiation; Signal transduction; Programmed cell death.