基于eet的治疗减轻索拉非尼相关的肾小球细胞损伤。

IF 4.8 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biomolecules Pub Date : 2025-09-16 DOI:10.3390/biom15091324

Abhishek Mishra, Marcus de Bourg, Rawand S Mohamed, Md Abdul Hye Khan, Tsigereda Weldemichael, Donald J Johann, Samaneh Goorani, Shobanbabu Bommagani, Darin E Jones, Anders Vik, John D Imig

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引用次数: 0

摘要

背景：本研究探讨索拉非尼如何诱导肾小球细胞毒性，并研究8,9-环氧二碳三烯酸（8,9- eet）类似物在减轻肾损害中的保护作用。方法：对人肾系膜细胞（HRMCs）和足细胞进行不加治疗、单用索拉非尼或索拉非尼联合8,9- eet类似物治疗。测定两种细胞类型的细胞活力和凋亡。结果：索拉非尼（1-10µM）降低hrmc和足细胞的细胞活力，增加caspase 3/7活性，呈剂量依赖性。在20种8,9- eet类似物中，有5种能显著提高细胞存活率，减少细胞凋亡。RNA测序显示，索拉非尼改变了1244个基因，包括参与细胞周期和Raf/MEK/ERK通路的基因。8,9- eet类似物MDB-52a提高了与代谢和血管健康相关的ANGPTL4水平，并降低了可能激活保护性途径的ACTA2。Nephroseq数据将这些基因改变与肾小球硬化联系起来。结论：MDB-52似乎可以抵消基因破坏并防止索拉非尼引起的肾损害。总之，靶向肾小球细胞的8,9- eet类似物可能是减轻索拉非尼相关肾毒性的潜在治疗剂。

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EET-Based Therapeutics Mitigate Sorafenib-Associated Glomerular Cell Damage.

Background: This study investigates how sorafenib induces toxicity in glomerular cells and examines the protective role of 8,9-epoxyeicosatrienoic acid (8,9-EET) analogs in reducing this kidney damage.

Methods: Human renal mesangial cells (HRMCs) and podocytes were treated with no treatment, sorafenib alone, or sorafenib combined with 8,9-EET analogs. Cell viability and apoptosis were measured in both cell types.

Results: Sorafenib (1-10 µM) lowered cell viability and increased caspase 3/7 activity in a dose-dependent way in HRMCs and podocytes. Five of twenty 8,9-EET analogs significantly enhanced cell survival and decreased apoptosis. RNA sequencing showed that sorafenib altered 1244 genes, including those involved in cell cycle and the Raf/MEK/ERK pathway. The 8,9-EET analog MDB-52a raised ANGPTL4 levels, linked to metabolism and vascular health, and reduced ACTA2, which could activate protective pathways. Nephroseq data correlated these gene changes with glomerulosclerosis.

Conclusions: MDB-52 appears to counteract gene disruptions and protect against sorafenib-induced kidney damage. Overall, 8,9-EET analogs targeting glomerular cells could be potential therapeutic agents to lessen sorafenib-related nephrotoxicity.

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来源期刊

Biomolecules Biochemistry, Genetics and Molecular Biology-Molecular Biology

CiteScore

9.40

自引率

3.60%

发文量

1640

审稿时长

18.28 days

期刊介绍： Biomolecules (ISSN 2218-273X) is an international, peer-reviewed open access journal focusing on biogenic substances and their biological functions, structures, interactions with other molecules, and their microenvironment as well as biological systems. Biomolecules publishes reviews, regular research papers and short communications. Our aim is to encourage scientists to publish their experimental and theoretical results in as much detail as possible. There is no restriction on the length of the papers. The full experimental details must be provided so that the results can be reproduced.