Sinapic acid modulates Nrf2/HO-1 signaling pathway in cisplatin-induced nephrotoxicity in rats
Sinapic acid modulates Nrf2/HO-1 signaling pathway in cisplatin-induced nephrotoxicity in rats
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DOI：
10.1016/j.biopha.2017.06.085
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发表时间：
2017-09-01
影响因子：
7.5
通讯作者：
Ansari, Mushtaq Ahmad
中科院分区：
文献类型：
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作者：
Ansari, Mushtaq Ahmad
背景：顺铂引起的肾毒性与肾脏活性氧和炎症细胞因子的增加有关。Sinapic acid （SA）具有抗氧化和抗炎活性。目的：我们确定了SA对大鼠顺铂诱导的肾毒性的影响，以及其增强抗氧化反应和减轻氧化/亚硝化应激、细胞凋亡和炎症相关肾毒性的潜在机制。方法:肾功能标志物（如血清尿素、尿酸、肌酐和乳酸脱氢酶）、氧化应激标志物（如脂质过氧化和一氧化氮）、抗氧化系统（如超氧化物歧化酶、过氧化氢酶和还原性谷胱甘肽）、炎症标志物（如肿瘤坏死因子- α [tnf - α]、白细胞介素-6 [IL-6]和髓过氧化物酶[MPO]）、凋亡标志物（caspase 3、Bax和Bcl-2）、核因子- kb （nf - κ B [p65]）、Nrf2水平、血红素加氧酶-1 （HO-1）。肾脏的组织病理学检查也用于评估顺铂引起的肾毒性。主要发现：SA（10和20 mg/kg）预处理改善了顺铂注射大鼠的肾功能，上调了抗氧化水平，下调了脂质过氧化和一氧化氮水平，导致氧化应激和内源性抗氧化酶的补充显著减少。顺铂上调细胞因子（即tnf - α和IL-6）和MPO，增加细胞凋亡，下调Nrf2和HO-1。SA预处理下调促凋亡caspase-3和Bax蛋白，上调抗凋亡Bcl-2蛋白。SA预处理还可减轻肾小管组织损伤程度，减少中性粒细胞浸润。意义：结果表明Nrf2/HO-1信号通路可能是SA保护顺铂诱导肾毒性的主要靶点，SA通过抑制NF-kappa B. (C) 2017 Elsevier Masson SAS降低氧化应激、炎症和细胞凋亡。版权所有。
Background: Cisplatin-induced nephrotoxicity is related to increased reactive oxygen species and inflammatory cytokines in the kidney. Sinapic acid (SA) has both antioxidant and anti-inflammatory activities.Aims: We determined the effects of SA on cisplatin-induced nephrotoxicity in rats, and the potential mechanisms by which it augments antioxidant responses and attenuates nephrotoxicity related to oxidative/nitrosative stress, apoptosis, and inflammation.Methods: Kidney function markers (i.e., serum urea, uric acid, creatinine, and lactate dehydrogenase), oxidative stress markers (i.e., lipid peroxidation and nitric oxide), antioxidant systems (i.e., superoxide dismutase, catalase, and reduced glutathione), inflammation markers (i.e., tumor necrosis factor-alpha[TNF-alpha], interleukin-6 [IL-6], and myeloperoxidase [MPO]), apoptotic markers (caspase 3, Bax, and Bcl-2), and the levels of nuclear factor-kB (NF-kappa B [p65]), Nrf2, and heme oxygenase-1 (HO-1) were assessed. Histopathological examinations of the kidney were also used to evaluate cisplatin-induced nephrotoxicity.Key findings: SA (10 and 20 mg/kg) pretreatment ameliorated kidney function, upregulated antioxidant levels, and downregulated lipid peroxidation and nitric oxide levels in cisplatin-injected rats, resulting in significant reductions in oxidative stress and replenishment of endogenous antioxidant enzymes. Cisplatin upregulated cytokines (i.e., TNF-alpha and IL-6) and MPO, increased apoptosis, and downregulated Nrf2 and HO-1. SA pretreatment downregulated the pro-apoptotic caspase-3 and Bax proteins, and upregulated the anti-apoptotic Bcl-2 protein. SA pretreatment also alleviated the extent of histological impairment and reduced neutrophil infiltration in renal tubules.Significance: The results suggest that the Nrf2/HO-1 signaling pathway may be the primary target for protection from cisplatin-induced nephrotoxicity by SA, and that SA reduces oxidative stress, inflammation, and apoptosis by inhibiting NF-kappa B. (C) 2017 Elsevier Masson SAS. All rights reserved.