Paeonol ameliorates diabetic nephropathy by promoting TFEB-mediated lysosome biogenesis and lipophagy

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine Pub Date : 2025-05-24 DOI:10.1016/j.phymed.2025.156901

Sinan Ai , Jiayin Tao , Yaoxian Wang , Jingwei Zhou , Weijing Liu , Xi Li , Lin Wang , Jinyi Hou , Leying Zhao , Zhen Wang , Liang Peng

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引用次数: 0

Abstract

Rationale

Diabetic nephropathy (DN) is a significant clinical and public health burden worldwide whose magnitude underscores the urgent need for more effective treatment options. Excessive lipid accumulation in renal tubular cells leads to their injury and dysfunction, thereby contributing to DN progression, suggesting that the alleviation of renal tubular lipid accumulation is a potential strategy for treating DN.

Methods

The effects of paeonol (PAE), a natural phenolic compound, on renal tubular lipid accumulation were evaluated using a glucolipotoxicity-treated HK-2 cell line and C57BL/6 J mice treated with streptozotocin (STZ) injection combined with a high-fat diet (HFD). Autophagic flux and lipophagy were assessed through immunofluorescence, adenoviral mRFP-GFP-LC3 transfection, and western blotting. Small interfering RNA (siRNA) was used for in vitro experiments to silence Tfeb in HK-2 cells, while a Cre-loxP system was employed to induce Tfeb knockout specifically in renal tubules in vivo, to validate the therapeutic target of PAE. RNA sequencing, pulldown assays, surface plasmon resonance (SPR), and molecular docking were utilized to further explore the specific molecular mechanisms involved.

Results

We found that PAE dose-dependently alleviated renal tubular lipid accumulation in glucolipotoxicity-treated HK-2 cells and the DN mouse model. Mechanistically, PAE directly binds to RHEB, functioning as an mTOR suppressor, thereby activating TFEB to promote lysosome biogenesis and lipophagy, subsequently alleviating renal tubular lipid accumulation and DN progression.

Conclusions

Per our findings, PAE holds promise as a therapeutic agent for DN, with the unique mechanism of activating renal TFEB-mediated lipophagy.

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丹皮酚通过促进tfeb介导的溶酶体生物生成和脂质吞噬来改善糖尿病肾病

糖尿病肾病（DN）是全球重大的临床和公共卫生负担，其严重程度强调了迫切需要更有效的治疗方案。肾小管细胞脂质积累过多导致其损伤和功能障碍，从而促进DN的进展，提示减轻肾小管脂质积累是治疗DN的潜在策略。方法采用链脲佐菌素（STZ）联合高脂饮食（HFD）处理的HK-2细胞和C57BL/6 J小鼠，观察天然酚类化合物丹皮酚（PAE）对肾小管脂质积累的影响。通过免疫荧光、腺病毒mRFP-GFP-LC3转染和western blotting检测自噬通量和脂噬情况。体外实验采用小干扰RNA （Small interfering RNA, siRNA）沉默HK-2细胞中的Tfeb，体内实验采用Cre-loxP系统诱导肾小管特异性敲除Tfeb，验证PAE的治疗靶点。利用RNA测序、拉下实验、表面等离子体共振（SPR）和分子对接等方法进一步探讨了其具体的分子机制。结果我们发现PAE剂量依赖性地减轻糖脂中毒HK-2细胞和DN小鼠模型的肾小管脂质积累。从机制上讲，PAE直接与RHEB结合，作为mTOR抑制因子，从而激活TFEB，促进溶酶体的生物生成和脂质吞噬，从而减轻肾小管脂质积累和DN的进展。结论根据我们的研究结果，PAE具有激活肾tfeb介导的脂质吞噬的独特机制，有望成为DN的治疗药物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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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.