Asiatic acid protects against cisplatin-induced acute kidney injury via anti-apoptosis and anti-inflammation
Asiatic acid protects against cisplatin-induced acute kidney injury via anti-apoptosis and anti-inflammation
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积雪草酸通过抗凋亡和抗炎作用预防顺铂引起的急性肾损伤
DOI：
10.1016/j.biopha.2018.08.126
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发表时间：
2018-11-01
影响因子：
7.5
通讯作者：
Liu, Hua-feng
中科院分区：
文献类型：
--
作者：
Yang, Chen;Guo, Yun;Liu, Hua-feng
顺铂是一种著名的化疗药物，用于治疗许多人类癌症。然而，临床上顺铂的使用受到一些严重副作用的限制，如肾毒性。不幸的是，目前还没有有效的治疗方法来预防顺铂诱导的AKI。越来越多的证据表明，小管上皮细胞凋亡和肾脏炎症主要决定顺铂诱导AKI的进展和结局。亚细亚酸（AA）具有抗炎症、抗细胞凋亡等功能。但AA对顺铂所致肾损伤的影响尚不清楚。本研究旨在确定AA对顺铂所致肾损伤的潜在保护作用。将24只C57BL/6雄性小鼠随机分为正常对照组（CON）、顺铂诱导AKI （CIS）、50 mg/kg AA预处理AKI （CIS + AA50）、100 mg/kg AA预处理AKI (CIS + AA100) 4组。小鼠注射顺铂后72 h麻醉处死。采集血液和肾脏样本进行分析。与对照组相比，顺铂治疗小鼠表现出严重的肾小管坏死和血清肌酐水平升高。而AA预处理（50 mg/kg或100 mg/kg）可显著抑制血清肌酐、尿素氮升高及组织学改变。此外，AA预处理显著下调肾小管损伤分子1 （KIM-1）的表达和凋亡细胞的数量，上调凋亡抑制剂survivin的表达，促进肾小管增殖，增殖细胞核抗原阳性细胞的数量增加。此外，AA抑制了肾脏促炎因子IL-1 β、tnf - α、MCP-1和caspase-1 mRNA表达的增加。此外，AA预处理可抑制NF-kappa B的激活和炎症反应，这可能与Smad7上调有关。综上所述，AA对顺铂诱导的AKI具有抗凋亡和抗炎症的保护作用。
Cisplatin is a well-known chemotherapeutic drug applied for the treatment of numerous human cancers. However, the use of cisplatin in clinic is limited by certain serious side effects, such as nephrotoxicity. Unfortunately, there is currently no effective therapeutic approach to prevent cisplatin-induced AKI. Increasing evidence suggests that apoptosis of tubular epithelial cells and renal inflammation mainly determine the progression and outcome of cisplatin-induced AKI. Asiatic acid (AA) has been reported have the functions of anti-inflammation and antiapoptosis, etc. But the effects of AA on kidney injury induced by cisplatin are still not known. The current study aimed to determine the potential renoprotective effects of AA on kidney injury induced by cisplatin. Twenty-four C57BL/6 male mice were randomly divided into four groups: normal control (CON), cisplatin-induced AKI (CIS), AKI with 50 mg/kg AA pretreatment (CIS + AA50), and AKI with 100 mg/kg AA pretreatment (CIS + AA100). Mice were anesthetized and sacrificed at 72 h after the cisplatin injection. Blood and kidney samples were collected for analyses. Compared with CON mice, cisplatin-treated mice exhibited severe tubular necrosis and elevated serum creatinine level. However, AA pretreatment (50 mg/kg or 100 mg/kg) markedly suppressed the elevated serum creatinine, blood urea nitrogen and histological changes. Moreover, AA pretreatment notably down-regulated tubular expression of kidney injury molecule-1 (KIM-1) and the number of apoptotic cells, and upregulated the expression of the apoptosis inhibitor survivin and promoted tubular proliferation as evidenced by an increase in the number of proliferating cell nuclear antigen-positive cells. In addition, AA suppressed the enhanced mRNA expression of proinflammatory cytokines IL-1 beta, TNF-alpha, MCP-1 and caspase-1 in the kidneys. Furthermore, AA pretreatment inhibited NF-kappa B activation and the inflammatory response, which may result from Smad7 up-regulation. In conclusion, AA protects against cisplatin-induced AKI via anti-apoptosis and anti-inflammation.