Gunebakan Evrin, Yalcin Esra, Dulger Esra Cikler, Yigitbasi Ahmet, Ates Nilay, Caglayan Aysun, Beker Mustafa C, Sahin Kazim, Korkaya Hasan, Kilic Ertugrul
Department of Physiology, School of Medicine, Istanbul Medipol University, Istanbul 34810, Turkey.
Department of Histology and Embryology, Hamidiye Medical School, University of Health Sciences, Istanbul 34668, Turkey.
Biomedicines. 2020 Feb 3;8(2):23. doi: 10.3390/biomedicines8020023.
Cisplatin (CP) is one of the most preferred platinum-containing antineoplastic drugs. However, even in nontoxic plasma concentrations, it may cause kidney injury. To be able to increase its effective pharmacological dose, its side effects need to be regarded. Diet restriction (DR) has been demonstrated to improve cellular survival in a number of disorders. In this context, we investigated the role of DR in CP-induced nephrotoxicity (CPN). Besides alternate DR, animals were exposed to DR for 3 days prior or after CP treatment. Here, we observed that both 3 days of DR reverses the nephrotoxic effect of CP, which was associated with improved physiological outcomes, such as serum creatine, blood-urea nitrogen and urea. These treatments significantly increased phosphorylation of survival kinases PI3K/Akt and ERK-1/2 and decreased the level of stress kinase JNK were noted. In addition, the activation level of signal transduction mediator p38 MAPK phosphorylation was higher particularly in both three-day DR groups. Next, animals were fed with carbohydrate-, protein- or fat-enriched diets in the presence of CP. Results indicated that not only fasting but also dietary content itself may play a determinant role in the severity of CPN. Our data suggest that DR is a promising approach to reduce CPN by regulating metabolism and cell signaling pathways.
顺铂（CP）是最常用的含铂抗肿瘤药物之一。然而，即使在无毒的血浆浓度下，它也可能导致肾损伤。为了能够增加其有效药理剂量，需要考虑其副作用。饮食限制（DR）已被证明可改善多种疾病中的细胞存活率。在此背景下，我们研究了DR在顺铂诱导的肾毒性（CPN）中的作用。除了交替饮食限制外，动物在顺铂治疗前或后3天接受饮食限制。在此，我们观察到3天的饮食限制均可逆转顺铂的肾毒性作用，这与血清肌酐、血尿素氮和尿素等生理指标的改善有关。这些治疗显著增加了存活激酶PI3K/Akt和ERK-1/2的磷酸化水平，并降低了应激激酶JNK的水平。此外，信号转导介质p38 MAPK磷酸化的激活水平尤其在两个三天饮食限制组中更高。接下来，在存在顺铂的情况下，给动物喂食富含碳水化合物、蛋白质或脂肪的饮食。结果表明，不仅禁食，而且饮食成分本身可能在CPN的严重程度中起决定性作用。我们的数据表明，饮食限制是通过调节代谢和细胞信号通路来减轻CPN的一种有前景的方法。
