lithosperate镁B通过调节KLF5/CDK1/Cyclin B1通路防止缺血性aki向ckd进展

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine Pub Date : 2025-04-14 DOI:10.1016/j.phymed.2025.156765

Liyu Lin , Daoqi Shen , Yiqi Su , Zhen Zhang , Jinbo Yu , Chenqi Xu , Kunming Pan , Yaqiong Wang , Lin Zhang , Shi Jin , Nana Song , Xiaoqiang Ding , Jie Teng , Xialian Xu

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引用次数: 0

摘要

缺血再灌注损伤（IRI）是急性肾损伤（AKI）的主要原因，急性肾损伤可导致慢性肾脏疾病（CKD）伴肾纤维化。石精镁B （Mlb）是一种从丹参中提取的生物活性化合物，对AKI具有肾保护作用。然而，Mlb在CKD患者iri诱导AKI演变中的意义尚不清楚。值得注意的是，在这一进展过程中，Mlb抗纤维化活性的具体机制仍有待充分阐明。目的：本研究旨在探讨Mlb在aki - ckd进展中的治疗益处，并揭示其潜在机制，特别关注其对肾纤维化和细胞周期调节的影响。研究设计与方法采用单侧缺血再灌注（UIR）诱导小鼠AKI-to-CKD进展（体内）和TGF-β-诱导的HK-2细胞纤维化模型（体外）。通过组织学分析、分子分析、网络药理学和RNA测序研究了Mlb对肾纤维化和细胞周期相关信号通路的有益作用。结果在uir诱导的AKI后14天，smlb治疗可显著减轻小鼠肾功能障碍、炎症、细胞凋亡和G2/M期细胞周期阻滞，随后改善肾纤维化。从机制上讲，Mlb促进CDK1/Cyclin B1信号通路的活性，从而缓解G2/M期细胞周期阻滞。网络药理学和RNA测序分析确定了KLF5/CDK1/Cyclin B1信号通路是Mlb抗纤维化作用的潜在靶点，这在体内和体外实验中得到了进一步的验证。KLF5抑制剂ML264通过降低CDK1/Cyclin B1表达和恢复G2/M期细胞周期停滞来减弱Mlb的保护作用，突出了该途径在Mlb介导的肾保护中的关键作用。结论在aki向ckd进展过程中，smlb通过KLF5/CDK1/Cyclin B1信号通路抑制G2/M期细胞周期阻滞，从而减少肾纤维化。我们的研究结果为Mlb在预防AKI后CKD进展方面的治疗潜力提供了新的见解，并确定了先前未被认识的涉及KLF5/CDK1/Cyclin B1途径的机制。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Magnesium Lithospermate B Protects Against Ischemic AKI-to-CKD progression via regulating the KLF5/CDK1/Cyclin B1 pathway

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Magnesium Lithospermate B Protects Against Ischemic AKI-to-CKD progression via regulating the KLF5/CDK1/Cyclin B1 pathway

Background

Ischemia-reperfusion injury (IRI) is the primary cause of acute kidney injury (AKI), which can result in chronic kidney disease (CKD) with renal fibrosis. Magnesium lithospermate B (Mlb), a bioactive compound produced from Salvia miltiorrhiza Bunge, exerts nephroprotective effects against AKI. However, the significance of Mlb in the evolution of IRI-induced AKI in patients with CKD remains unclear. Notably, the specific mechanisms underlying the putative antifibrotic activities of Mlb during this progression remain to be fully elucidated.

Purpose

This study sought to explore the therapeutic benefits of Mlb in AKI-to-CKD progression and uncover the potential mechanisms, with a special interest in its effects on renal fibrosis and cell cycle regulation.

Study design and methods

Unilateral ischemia/reperfusion (UIR)-induced mouse AKI-to-CKD progression (in vivo) and HK-2 cells with TGF-β-induced fibrosis model (in vitro) were used in the study. The beneficial effects of Mlb on renal fibrosis and cell cycle-related signaling pathways were investigated using histological analysis, molecular assays, network pharmacology, and RNA sequencing.

Results

Mlb treatment significantly reduced renal dysfunction, inflammation, apoptosis, and the G2/M phase cell cycle stalling in mice 14 days post-UIR-induced AKI, subsequently improving renal fibrosis. Mechanistically, Mlb promotes the activity of the CDK1/Cyclin B1 signaling pathway, thereby alleviating the G2/M phase cell cycle stalling. Network pharmacology and RNA sequencing analyses identified the KLF5/CDK1/Cyclin B1 signaling pathway as a potential target of the antifibrotic effects of Mlb, which was further verified in both in vivo and in vitro experiments. The KLF5 inhibitor ML264 attenuated the protective effects of Mlb by reducing CDK1/Cyclin B1 expression and reinstating the G2/M phase cell cycle stalling, highlighting the critical role of this pathway in Mlb-mediated renal protection.

Conclusions

Mlb decreases renal fibrosis by inhibiting the G2/M phase cell cycle stalling via the KLF5/CDK1/Cyclin B1 signaling pathway during AKI-to-CKD progression. Our findings offer new insight into the therapeutic potential of Mlb in preventing CKD progression following AKI and identify a previously unrecognized mechanism involving the KLF5/CDK1/Cyclin B1 pathway.

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来源期刊

Phytomedicine 医学-药学

CiteScore

10.30

自引率

5.10%

发文量

670

审稿时长

91 days

期刊介绍： Phytomedicine is a therapy-oriented journal that publishes innovative studies on the efficacy, safety, quality, and mechanisms of action of specified plant extracts, phytopharmaceuticals, and their isolated constituents. This includes clinical, pharmacological, pharmacokinetic, and toxicological studies of herbal medicinal products, preparations, and purified compounds with defined and consistent quality, ensuring reproducible pharmacological activity. Founded in 1994, Phytomedicine aims to focus and stimulate research in this field and establish internationally accepted scientific standards for pharmacological studies, proof of clinical efficacy, and safety of phytomedicines.