PDF(Pubmed)
Abstract：
Cisplatin is an effective chemotherapeutic agent widely used for the treatment of various solid tumors. However, cisplatin has an important limitation in its use; currently, there is no method to ameliorate cisplatin-induced acute kidney injury (AKI). Thrombomodulin (TM) is well known not only for its role as a cofactor in the clinically important natural anticoagulation pathway but also for its anti-inflammatory properties. Here, we investigated the effects of TM in cisplatin-induced AKI. In mice intraperitoneally injected with 15 mg/kg cisplatin, TM (10 mg/kg) or PBS was administered intravenously at 24 h after cisplatin injection. TM significantly attenuated cisplatin-induced nephrotoxicity with the suppressed elevation of blood urea nitrogen and serum creatinine, and reduced histological damages. Actually, TM treatment significantly alleviated oxidative stress-induced apoptosis by reducing reactive oxygen species (ROS) levels in cisplatin-treated renal proximal tubular epithelial cells (RPTECs) in vitro. Furthermore, TM clarified cisplatin-induced apoptosis by reducing caspase-3 levels. In addition, TM attenuated the endoplasmic reticulum (ER) stress signaling pathway in both renal tissues and RPTECs to protect the kidneys from cisplatin-induced AKI. These findings suggest that TM is a potential protectant against cisplatin-induced nephrotoxicity through suppressing ROS generation and ER stress in response to cisplatin.
摘要：
顺铂是一种有效的化疗药物，广泛用于治疗各种实体瘤。然而,顺铂在使用上有一个重要的局限性；目前，目前尚无改善顺铂诱导的急性肾损伤（AKI）的方法。血栓调节蛋白（TM）不仅因其在临床上重要的天然抗凝血途径中作为辅因子的作用而广为人知，而且还因其抗炎特性而闻名。这里,我们研究了TM在顺铂诱导的AKI中的作用。小鼠腹腔注射15mg/kg顺铂,在注射顺铂后24小时静脉内施用TM(10mg/kg)或PBS。TM可显着减弱顺铂诱导的肾毒性，并抑制血尿素氮和血清肌酐的升高，减少组织学损伤。事实上,TM治疗通过降低体外顺铂治疗的肾近曲小管上皮细胞（RPTEC）中的活性氧（ROS）水平可显着减轻氧化应激诱导的细胞凋亡。此外，TM通过降低caspase-3水平阐明顺铂诱导的细胞凋亡。此外,TM减弱了肾组织和RPTEC中的内质网（ER）应激信号通路，以保护肾脏免受顺铂诱导的AKI。这些发现表明，TM是一种潜在的保护剂，可以通过抑制顺铂引起的ROS产生和ER应激来抵抗顺铂引起的肾毒性。
