Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, China.
Department of Emergency, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, China.
Biomed Pharmacother. 2018 Nov;107:1354-1362. doi: 10.1016/j.biopha.2018.08.126. Epub 2018 Aug 30.
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 anti-apoptosis, 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 downregulated 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-1β, TNF-α, MCP-1 and caspase-1 in the kidneys. Furthermore, AA pretreatment inhibited NF-κB 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.
顺铂是一种广泛应用于多种人类癌症治疗的化疗药物。然而，顺铂在临床上的应用受到某些严重副作用的限制，如肾毒性。不幸的是，目前尚无有效的治疗方法来预防顺铂引起的 AKI。越来越多的证据表明，肾小管上皮细胞凋亡和肾脏炎症主要决定了顺铂诱导的 AKI 的进展和结局。齐墩果酸（AA）已被报道具有抗炎和抗凋亡等功能。但是，AA 对顺铂引起的肾损伤的作用尚不清楚。本研究旨在确定 AA 对顺铂诱导的肾损伤的潜在保护作用。将 24 只 C57BL/6 雄性小鼠随机分为四组：正常对照组（CON）、顺铂诱导的 AKI 组（CIS）、顺铂预处理 50mg/kgAA 组（CIS+AA50）和顺铂预处理 100mg/kgAA 组（CIS+AA100）。顺铂注射后 72 小时麻醉处死小鼠，采集血液和肾脏样本进行分析。与 CON 组小鼠相比，顺铂处理组小鼠表现出严重的肾小管坏死和血清肌酐水平升高。然而，AA 预处理（50mg/kg 或 100mg/kg）显著抑制了升高的血清肌酐、血尿素氮和组织学变化。此外，AA 预处理显著下调了肾小管损伤分子-1（KIM-1）的表达和凋亡细胞的数量，并上调了凋亡抑制剂生存素的表达，通过增加增殖细胞核抗原阳性细胞的数量促进了肾小管增殖。此外，AA 抑制了肾脏中促炎细胞因子 IL-1β、TNF-α、MCP-1 和 caspase-1 的 mRNA 表达增强。此外，AA 预处理抑制了 NF-κB 激活和炎症反应，这可能是由于 Smad7 的上调。综上所述，AA 通过抗凋亡和抗炎作用来保护顺铂诱导的 AKI。
