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Short-Term Diet Restriction but Not Alternate Day Fasting Prevents Cisplatin-Induced Nephrotoxicity in Mice.

ABSTRACT: 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.

SUBMITTER: Gunebakan E

PROVIDER: S-EPMC7168297 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Short-Term Diet Restriction but Not Alternate Day Fasting Prevents Cisplatin-Induced Nephrotoxicity in Mice.

Gunebakan Evrin E Yalcin Esra E Dulger Esra Cikler EC Yigitbasi Ahmet A Ates Nilay N Caglayan Aysun A Beker Mustafa C MC Sahin Kazim K Korkaya Hasan H Kilic Ertugrul E

Biomedicines 20200203 2

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 da ...[more]

PMID: 32028692

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Project description:BackgroundThe administration of cisplatin is limited due to its nephrotoxic side effects, and prevention of this nephrotoxicity of cisplatin is difficult. Mesenchymal stem cell (MSC)-derived exosomes have been implicated as a novel therapeutic approach for tissue injury. In this study, we demonstrated that the pretreatment of human umbilical cord MSC-derived exosomes (hucMSC-Ex) can prevent the development of cisplatin-induced renal toxicity by activation of autophagy in vitro and in vivo.MethodsIn vitro, rat renal tubular epithelial (NRK-52E) cells were pre-incubated with exosomes from hucMSC or HFL1 (human lung fibroblast cells; as control) for 30 min, and 3-methyladenine (an autophagic inhibitor) and rapamycin (an autophagic inducer) for 1 h before cisplatin treatment for 8 h, respectively. Cells were harvested for apoptosis assay, enzyme-linked immunosorbent assay (ELISA), Western blot, and quantitative real-time polymerase chain reaction (qRT-PCR). In vivo, we constructed cisplatin-induced acute kidney injury rat models. Prior to treatment with cisplatin for 0.5 h, hucMSC-Ex or HFL1-Ex were injected into the kidneys via the renal capsule. 3-methyladenine and rapamycin were injected under the kidney capsule before hucMSC-Ex. All animals were sacrificed at 3 days after cisplatin injection. Renal function, Luminex assay, tubular apoptosis and proliferation, and autophagy response were evaluated.ResultshucMSC-Ex inhibited cisplatin-induced mitochondrial apoptosis and secretion of inflammatory cytokines in renal tubular epithelial cells in vitro. hucMSC-Ex increased the expression of the autophagic marker protein LC3B and the autophagy-related genes ATG5 and ATG7 in NRK-52E cells. Rapamycin mimicked the effects of hucMSC-Ex in protecting against cisplatin-induced renal injury, while the effects were abrogated by the autophagy inhibitor 3-methyladenine in the animals.ConclusionsOur findings indicate that the activation of autophagy induced by hucMSC-Ex can effectively relieve the nephrotoxicity of cisplatin. Therefore, pre-treatment of hucMSC-Ex may be a new method to improve the therapeutic effect of cisplatin.

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Short-Term Diet Restriction but Not Alternate Day Fasting Prevents Cisplatin-Induced Nephrotoxicity in Mice.

Publications

Short-Term Diet Restriction but Not Alternate Day Fasting Prevents Cisplatin-Induced Nephrotoxicity in Mice.

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