Effect of SMTP-7 on Cisplatin-Induced Nephrotoxicity in Mice
Effect of SMTP-7 on Cisplatin-Induced Nephrotoxicity in Mice
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DOI：
10.1248/bpb.b22-00620
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发表时间：
2022-12-01
影响因子：
2
通讯作者：
Nobe, Koji
中科院分区：
文献类型：
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作者：
Hashimoto, Terumasa;Shibata, Keita;Nobe, Koji
SMTP-7是一种真菌代谢产物，据报道对缺血再灌注（IR）诱导的急性肾损伤（阿基）模型具有高度的可用性。顺铂是一种广泛使用的抗癌药物，具有严重的副作用，如阿基。因此，我们在本研究中旨在检查SMTP-7对顺铂诱导的阿基的影响。静脉输注顺铂（20 mg/kg）后72 h，观察到血尿素氮（BUN）和血清肌酐（Scr）显著升高。组织学上，近端小管中观察到坏死和扩张（透明管型）以及再生。SMTP-7剂量依赖性地抑制顺铂引起的BUN和Scr升高。当在顺铂治疗后的第二天给予药物时，SMTP-7的疗效显著，而重复给予药物并未导致疗效增强。此外，10 mg/kg的SMTP-7显著改善肾小管坏死和扩张。顺铂治疗还导致肿瘤坏死因子-α（TNF-α）mRNA表达的上调之前，BUN和Scr的水平升高。在顺铂输注后24 h给予SMTP-7（10 mg/kg）缓解了TNF-α mRNA表达的上调。这些发现表明，SMTP-7基于抑制促炎细胞因子如TNF-α的表达而表现出对顺铂输注的肾保护作用，并且有望成为治疗顺铂诱导的阿基的新的有效药物。
SMTP-7, a fungal metabolite, is reported to have a high degree of availability for the ischemia-reperfusion ( IR)-induced acute kidney injury (AKI) model. Cisplatin, a widely used anticancer drug, has serious side effects, such as AKI. Hence, we aimed to examine the effect of SMTP-7 on cisplatin-induced AKI in this study. Significant increases in blood urea nitrogen (BUN) and serum creatinine (Scr) were observed at 72 h after the intravenous infusion of cisplatin (20 mg/kg). Histologically, necrosis and dilatation (hyaline casts) as well as regeneration were observed in proximal tubules. SMTP-7 inhibited the elevation on BUN and Scr caused by cisplatin dose dependently. The efficacy of SMTP-7 was notable when the drug was administered on the day after cisplatin treatment, whereas the repeated administration of the drug did not result in an enhanced efficacy. Moreover, 10 mg/kg of SMTP-7 considerably ameliorated tubular necrosis and dilatation. The cisplatin treatment also caused an up-regulation of tumor necrosis factor-alpha (TNF-alpha) mRNA expression prior to the elevation of the levels of BUN and Scr. Administration of SMTP-7 (10 mg/kg) at 24 h after the cisplatin infusion alleviated the up-regulation of TNF-alpha mRNA expression. These findings suggest that SMTP-7 exhibits a renoprotective effect against cisplatin infusion based on the inhibition of the expression of pro-inflammatory cytokines such as TNF-alpha and may be expected a new effective drug for the treatment of cisplatin-induced AKI.