Lipid imaging for visualizing cilastatin amelioration of cisplatin-induced nephrotoxicity
Lipid imaging for visualizing cilastatin amelioration of cisplatin-induced nephrotoxicity
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DOI：
10.1194/jlr.m080465
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发表时间：
2018-09-01
影响因子：
6.5
通讯作者：
Milagros Gomez-Gomez, M.
中科院分区：
文献类型：
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作者：
Moreno-Gordaliza, Estefania;Esteban-Fernandez, Diego;Milagros Gomez-Gomez, M.
肾毒性是顺铂抗肿瘤治疗的主要限制。西司他汀是一种肾脱氢肽酶- i抑制剂，最近被认为是一种有前途的抗顺铂毒性的肾保护剂，可以防止细胞凋亡。在这项工作中，西司他汀在大鼠模型中进一步研究了其对76种顺铂改变的肾脂质的影响，其中包括13种新的顺铂改变的线粒体心磷脂。用MALDI质谱成像（MALDI- msi）对治疗大鼠肾切片进行脂质成像。西司他汀被证明可以显著减少顺铂引起的脂质分布改变，脂质水平几乎完全恢复到对照组的水平。西司他汀恢复顺铂改变的脂质的程度被证明与区分顺铂驱动的直接或继发性脂质改变有关。使用西司他汀后，顺铂引起的脂质过氧化反应也有所减少。重要的是，在皮质脂质和髓外脂质多变量分析中实现了显著的组分离，这表明可以从肾保护组和健康组中区分出受损肾脏，并根据脂质分布进行分类。因此，我们建议MALDI-MSI作为一种强大的潜在工具，提供基于脂质分析的多分子检测可能性，以可视化和评估肾毒性和肾保护。
Nephrotoxicity is a major limitation to cisplatin antitumor therapies. Cilastatin, an inhibitor of renal dehydropeptidase-I, was recently proposed as a promising nephroprotector against cisplatin toxicity, preventing apoptotic cell death. In this work, cilastatin nephroprotection was further investigated in a rat model, with a focus on its effect on 76 renal lipids altered by cisplatin, including 13 new cisplatin-altered mitochondrial cardiolipin species. Lipid imaging was performed with MALDI mass spectrometry imaging (MALDI-MSI) in kidney sections from treated rats. Cilastatin was proved to significantly diminish the lipid distribution alterations caused by cisplatin, lipid levels being almost completely recovered to those of control samples. The extent of recovery of cisplatin-altered lipids by cilastatin turned out to be relevant for discriminating direct or secondary lipid alterations driven by cisplatin. Lipid peroxidation induced by cisplatin was also shown to be reduced when cilastatin was administered. Importantly, significant groups separation was achieved during multivariate analysis of cortex and outer-medullary lipids, indicating that damaged kidney can be discerned from the nephroprotected and healthy groups and classified according to lipid distribution. Therefore, we propose MALDI-MSI as a powerful potential tool offering multimolecule detection possibilities to visualize and evaluate nephrotoxicity and nephroprotection based on lipid analysis.