Caloric Restriction Is More Efficient than Physical Exercise to Protect from Cisplatin Nephrotoxicity via PPAR-Alpha Activation.
Caloric Restriction Is More Efficient than Physical Exercise to Protect from Cisplatin Nephrotoxicity via PPAR-Alpha Activation.
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DOI：
10.3389/fphys.2017.00116
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发表时间：
2017
影响因子：
4
通讯作者：
Araujo RC
中科院分区：
文献类型：
--
作者：
Estrela GR;Wasinski F;Batista RO;Hiyane MI;Felizardo RJ;Cunha F;de Almeida DC;Malheiros DM;Câmara NO;Barros CC;Bader M;Araujo RC
抗肿瘤药物顺铂会促进肾损伤，从而限制了其使用。减少顺铂肾毒性的方案将允许在顺铂治疗中使用更高的剂量。在这里，我们比较了体育锻炼和热量限制（CR）作为减少小鼠顺铂肾损伤的方案。雄性C57BL/6分为四组：对照、顺铂、运动+顺铂和30% CR+顺铂。给动物注射单剂量的顺铂（20mg/kg i.p.）并在注射后96小时处死。通过实时定量 PCR、组织学分析、免疫组织化学和生化测量来研究肾损伤、坏死、细胞凋亡和炎症机制。两种方案均可防止顺铂肾损伤，但 CR 在减少尿毒症和肾坏死方面更有效。 CR+顺铂组表现出血清IL-1β和TNF-α水平降低。细胞因子的肾 mRNA 表达没有发现差异。两种干预措施均减少了细胞凋亡，但只有 CR + 顺铂组降低了 TNFR2 蛋白表达。 CR 后小鼠体内 PPAR-α 被激活。 PPAR-α 拮抗剂可阻断 CR 的保护作用。两种干预措施均减轻了顺铂注射引起的肾毒性，但 CR + 顺铂通过调节 TNFR2 显示出更好的反应。此外，部分 CR 益处取决于 PPAR-α 激活。
The antineoplastic drug cisplatin promotes renal injury, which limits its use. Protocols that reduce renal cisplatin toxicity will allow higher doses to be used in cisplatin treatment. Here, we compare physical exercise and caloric restriction (CR) as protocols to reduce cisplatin renal injury in mice. Male C57BL/6 were divided into four groups: Control, cisplatin, exercise + cisplatin, and 30% CR + cisplatin. Animals were injected with a single dose of cisplatin (20 mg/kg i.p.) and sacrificed 96 h after injection. Quantitative real time PCR, histological analyses, immunohistochemistry, and biochemical measurements were performed to investigate renal injury, necrosis, apoptosis, and inflammatory mechanisms. Both protocols protected against cisplatin renal injury, but CR was more effective in reducing uraemia and renal necrosis. The CR + Cisplatin group exhibited reduced serum IL-1β and TNF-α levels. No differences were noted in the renal mRNA expression of cytokines. Both interventions reduced apoptosis, but only the CR + Cisplatin group decreased TNFR2 protein expression. PPAR-α was activated in mice after CR. An antagonist of PPAR-α blocked the protective effect of CR. Both interventions attenuated the nephrotoxicity caused by cisplatin injection, but CR + Cisplatin showed a better response by modulating TNFR2. Moreover, part of the CR benefit depends on PPAR-α activation.