菊苣酸通过缓解PAQR3与P110α通路之间的相互作用,促进PAQR3泛素化,从而改善糖尿病肾病的铁变态反应。

IF 1.5 4区 医学 Q3 PERIPHERAL VASCULAR DISEASE Clinical and Experimental Hypertension Pub Date : 2024-12-31 Epub Date: 2024-03-25 DOI:10.1080/10641963.2024.2326021
Weiwei Zhang, Yong Liu, Jiajun Zhou, Teng Qiu, Haitang Xie, Zhichen Pu
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引用次数: 0

摘要

目的:本研究旨在探讨CA对DN的影响,并阐明其潜在的炎症分子机制:方法:我们给 C57BL/6 小鼠注射链脲佐菌素诱发糖尿病。此外,我们还用 20 mmol/L d-葡萄糖刺激 NRK-52E 细胞以模拟糖尿病状态:我们的研究结果表明,CA 能有效降低血糖水平,改善小鼠模型的 DN。此外,CA 还能减轻小鼠模型和体外模型中的肾损伤和炎症反应。CA通过诱导GSH/GPX4轴减少了高血糖诱导的NRK-52E细胞的铁突变。相反,在小鼠模型和体外模型中,铁突变激活剂或 PI3K 抑制剂逆转了 CA 对 DN 的积极作用。CA抑制了PAQR3在DN模型中的表达,从而促进了PI3K/AKT的活性。PAQR3 激活剂降低了 CA 在体外模型中对 DN 的积极影响。此外,CA直接靶向PAQR3蛋白,增强了PAQR3蛋白的泛素化:总之,我们的研究发现 CA 能促进 PAQR3 的泛素化,从而减弱 DN 中的铁突变。这种作用是通过破坏 PAQR3 与 P110α 通路之间的相互作用,激活 PI3K/AKT 信号通路实现的。这些发现凸显了 CA 作为预防 DN 和其他形式糖尿病的可行疗法的潜力。
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Chicoric acid advanced PAQR3 ubiquitination to ameliorate ferroptosis in diabetes nephropathy through the relieving of the interaction between PAQR3 and P110α pathway.

Purpose: This study aimed to examine the impact of CA on DN and elucidate its underlying molecular mechanisms of inflammation.

Methods: We fed C57BL/6 mice injected with streptozotocin to induce diabetes. In addition, we stimulated NRK-52E cells with 20 mmol/L d-glucose to mimic the diabetic condition.

Results: Our findings demonstrated that CA effectively reduced blood glucose levels, and improved DN in mice models. Additionally, CA reduced kidney injury and inflammation in both mice models and in vitro models. CA decreased high glucose-induced ferroptosis of NRK-52E cells by inducing GSH/GPX4 axis. Conversely, the ferroptosis activator or the PI3K inhibitor reversed positive effects of CA on DN in both mice and in vitro models. CA suppressed PAQR3 expression in DN models to promote PI3K/AKT activity. The PAQR3 activator reduced the positive effects of CA on DN in vitro models. Moreover, CA directly targeted the PAQR3 protein to enhance the ubiquitination of the PAQR3 protein.

Conclusion: Overall, our study has uncovered that CA promotes the ubiquitination of PAQR3, leading to the attenuation of ferroptosis in DN. This effect is achieved through the activation of the PI3K/AKT signaling pathways by disrupting the interaction between PAQR3 and the P110α pathway. These findings highlight the potential of CA as a viable therapeutic option for the prevention of DN and other forms of diabetes.

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来源期刊
CiteScore
3.90
自引率
0.80%
发文量
66
审稿时长
6-12 weeks
期刊介绍: Clinical and Experimental Hypertension is a reputable journal that has converted to a full Open Access format starting from Volume 45 in 2023. While previous volumes are still accessible through a Pay to Read model, the journal now provides free and open access to its content. It serves as an international platform for the exchange of up-to-date scientific and clinical information concerning both human and animal hypertension. The journal publishes a wide range of articles, including full research papers, solicited and unsolicited reviews, and commentaries. Through these publications, the journal aims to enhance current understanding and support the timely detection, management, control, and prevention of hypertension-related conditions. One notable aspect of Clinical and Experimental Hypertension is its coverage of special issues that focus on the proceedings of symposia dedicated to hypertension research. This feature allows researchers and clinicians to delve deeper into the latest advancements in this field. The journal is abstracted and indexed in several renowned databases, including Pharmacoeconomics and Outcomes News (Online), Reactions Weekly (Online), CABI, EBSCOhost, Elsevier BV, International Atomic Energy Agency, and the National Library of Medicine, among others. These affiliations ensure that the journal's content receives broad visibility and facilitates its discoverability by professionals and researchers in related disciplines.
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