Camel milk attenuates methotrexate-induced kidney injury via activation of PI3K/Akt/eNOS signaling and intervention with oxidative aberrations,Food & Function

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Camel milk attenuates methotrexate-induced kidney injury via activation of PI3K/Akt/eNOS signaling and intervention with oxidative aberrations
Food & Function ( IF 5.1 ) Pub Date : 2018-04-18 00:00:00 , DOI: 10.1039/c8fo00131f
Hany H. Arab _{1,

2,

3,

4,

5} , Samir A. Salama _{1,

2,

3,

4,

5} , Ibrahim A. Maghrabi _{3,

4,

5,

6,

7}

Affiliation

Methotrexate (MTX) is a classical chemotherapeutic agent with nephrotoxicity as the most disturbing adverse effect. So far, its underlying molecular mechanisms, particularly PI3K/Akt/eNOS transduction, are inadequately explored. Several antioxidant modalities have been characterized to ameliorate MTX-induced renal injury. In this regard, Camel milk (CM) is a natural product with recognized antioxidant and anti-inflammatory features. Thus, the current study aimed to investigate the potential ameliorating effects of CM in MTX-induced kidney injury in rats. Renal tissues were studied in terms of renal injury markers, histopathology, oxidative stress, apoptosis and PI3K/Akt/eNOS signaling. CM was orally administered (10 ml kg⁻¹) and the renal injury was induced by a single i.p. injection of MTX (20 mg kg⁻¹). Interestingly, CM dose-dependently attenuated MTX-triggered increase of BUN and serum creatinine and renal Kim-1 expression and mitigated the renal histopathological changes. CM counteracted renal oxidative stress as manifested by lowering of lipid peroxides, restoration of NOX-1 levels and augmentation of the antioxidant defenses e.g., GSH, SOD, GPx and total antioxidant capacity. With respect to apoptosis, CM curbed the cleavage of PARP and caspase-3, downregulated p53, Bax and Cyt C proapoptotic signals and enhanced Bcl-2 and PCNA levels. In the same context, CM activated the prosurvival PI3K/Akt/eNOS pathway via enhancing PI3K p110, phospho-Akt and phospho-eNOS levels. Equally important, CM preconditioning did not interfere with MTX cytotoxicity in TK-10 or PC-3 cancer cells. Together, the current findings demonstrate, for the first time, the renoprotective effects of CM in MTX-induced kidney injury via activation of PI3K/Akt/eNOS signaling and combating oxidative stress and apoptosis.

中文翻译：

骆驼奶通过激活PI3K / Akt / eNOS信号传导和氧化异常干预减轻甲氨蝶呤对肾脏的伤害

甲氨蝶呤（MTX）是一种经典的化学治疗剂，其肾毒性是最令人不安的不良反应。到目前为止，还没有充分研究其潜在的分子机制，特别是PI3K / Akt / eNOS的转导。已经表征了几种抗氧化剂形式以减轻MTX诱导的肾损伤。在这方面，骆驼奶（CM）是具有公认的抗氧化剂和抗发炎功能的天然产品。因此，当前的研究旨在研究CM在MTX诱导的大鼠肾脏损伤中的潜在改善作用。从肾损伤标志物，组织病理学，氧化应激，细胞凋亡和PI3K / Akt / eNOS信号传导方面研究了肾脏组织。口服给予CM（10 ml kg ^-1），单次腹膜内注射MTX（20 mg kg^-1）。有趣的是，CM剂量依赖性地减弱了MTX触发的BUN和血清肌酐和肾脏Kim-1表达的增加，并减轻了肾脏的组织病理学变化。CM抵消了肾脏的氧化应激，表现为脂质过氧化物的降低，NOX-1水平的恢复以及抗氧化防御素（例如GSH，SOD，GPx和总抗氧化能力）的增强。关于细胞凋亡，CM抑制了PARP和caspase-3的切割，下调了p53，Bax和Cyt C的凋亡信号，并增强了Bcl-2和PCNA的水平。在同样情况下，CM激活促存活PI3K / AKT / eNOS的通路通过增强PI3K p110，磷酸化Akt和磷酸化eNOS的水平。同样重要的是，CM预处理不会干扰TK-10或PC-3癌细胞中的MTX细胞毒性。总之，当前的发现首次证明了CM通过激活PI3K / Akt / eNOS信号并对抗氧化应激和细胞凋亡对MTX诱导的肾损伤的肾脏保护作用。

更新日期：2018-04-18

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