盐酸戊乙奎醚激活PARK2并调节AIFM1泛素化以挽救糖尿病肾病肾小管损伤。

IF 3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences Pub Date : 2025-02-01 DOI:10.1016/j.jphs.2024.12.001

Li Chen , Jing Tang , HongBao Tan

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引用次数: 0

摘要

背景：肾小管损伤（RTI）是糖尿病肾病（DN）的关键特征之一。盐酸戊乙基醚（PHC）是一种具有肾保护作用的抗胆碱能药物，但其治疗DN的具体机制尚不清楚。方法：采用PHC治疗不同的糖尿病小鼠模型和高糖RTI模型。采用流式细胞术和染色进行组织学分析，ELISA检测不同处理下的ROS、凋亡及相关标志物。通过ChIP、双荧光素酶报告基因和CoIP分析分子相互作用。结果：PHC通过激活线粒体自噬和抑制细胞凋亡来缓解RTI，并可通过下调PARK2来恢复其保护作用。Nrf2结合到PARK2的启动子区域，促进其表达。PHC通过降低AIFM1的核易位程度来降低细胞凋亡水平，而AIFM1是通过敲低PARK2来挽救的。PARK2敲低可降低AIFM1的非降解泛素化，从而促进其核易位，最终促进肾小管细胞（rtc）凋亡。AIFM1过表达可挽救PHC拮抗的rtc细胞凋亡。结论：PHC激活Nrf2上调PARK2转录，通过促进AIFM1的非降解泛素化，诱导线粒体自噬，抑制AIFM1核易位介导的细胞凋亡，最终挽救DN中的RTI。

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Penehyclidine hydrochloride activates PARK2 and modulates ubiquitination of AIFM1 to rescue renal tubular injury in diabetic kidney disease

Background

Renal tubular injury (RTI) is one of the key characteristics of diabetic nephropathy (DN). Penehyclidine hydrochloride (PHC) was an anticholinergic drug with renoprotective effects, but its specific mechanism in the treatment of DN was still unclear.

Methods

We treated different diabetic mouse models and high glucose-induced RTI models by PHC. Histological analyses were performed using flow cytometry and staining, and ELISA evaluated the ROS, apoptosis, and related markers under different treatments. The molecular interactions were analyzed by ChIP, dual-luciferase reporter, and CoIP.

Results

PHC alleviated RTI by activating mitophagy and inhibiting apoptosis, and the protective effect could be rescued by PARK2 knockdown. Nrf2 bound to the promoter region of PARK2 and promoted its expression. PHC reduced the level of apoptosis by reducing the degree of nuclear translocation of AIFM1, which was rescued by PARK2 knockdown. PARK2 knockdown reduced the non-degradative ubiquitination of AIFM1, thus promoting its nuclear translocation and ultimately facilitating renal tubular cells (RTCs) apoptosis. The over-expression of AIFM1 rescued the RTCs apoptosis antagonized by PHC.

Conclusions

PHC activated Nrf2 to up-regulate PARK2 transcription to induce mitophagy and inhibit apoptosis mediated by nuclear translocation of AIFM1 through promoting non-degradative ubiquitination of AIFM1, ultimately rescuing RTI in DN.

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来源期刊

Journal of pharmacological sciences 医学-药学

CiteScore

6.20

自引率

2.90%

发文量

104

审稿时长

31 days

期刊介绍： Journal of Pharmacological Sciences (JPS) is an international open access journal intended for the advancement of pharmacological sciences in the world. The Journal welcomes submissions in all fields of experimental and clinical pharmacology, including neuroscience, and biochemical, cellular, and molecular pharmacology for publication as Reviews, Full Papers or Short Communications. Short Communications are short research article intended to provide novel and exciting pharmacological findings. Manuscripts concerning descriptive case reports, pharmacokinetic and pharmacodynamic studies without pharmacological mechanism and dose-response determinations are not acceptable and will be rejected without peer review. The ethnopharmacological studies are also out of the scope of this journal. Furthermore, JPS does not publish work on the actions of biological extracts unknown chemical composition.