CD44-targeted hyaluronic acid-curcumin prodrug protects renal tubular epithelial cell survival from oxidative stress damage
CD44-targeted hyaluronic acid-curcumin prodrug protects renal tubular epithelial cell survival from oxidative stress damage
复制标题
CD44靶向透明质酸-姜黄素前药保护肾小管上皮细胞存活免受氧化应激损伤
DOI：
10.1016/j.carbpol.2018.04.011
复制
发表时间：
2018-08-01
影响因子：
11.2
通讯作者：
Du, Yong-Zhong
中科院分区：
文献类型：
--
作者：
Hu, Jing-Bo;Li, Shu-Juan;Du, Yong-Zhong
基于缺血/再灌注诱导的急性肾损伤（阿基）过程中肾小管上皮细胞CD 44受体表达异常增加，我们开发了一种靶向上皮细胞并减轻氧化应激损伤的透明质酸-姜黄素（HA-CUR）聚合物前药。HA-CUR的水溶性显著增强，约为CUR的27倍。细胞摄取实验表明，HA-CUR较游离CUR更易被H_2O_2预处理的HK-2细胞内化，这得益于HA与CD_（44）受体的特异性结合。生物分布结果进一步表明，HA-CUR在肾脏中的蓄积增加，是游离CUR的13.9倍。药效学研究表明HA-CUR能有效改善阿基，其确切机制是通过抑制PtdIns 3 K-AKT-mTOR信号通路保护肾小管上皮细胞免受氧化应激损伤。综上所述，本研究为基于疾病发病机制的阿基治疗提供了新的治疗策略。
Based on the abnormally increased expression of CD44 receptors on renal tubule epithelial cells during ischemia/reperfusion-induced acute kidney injury (AKI), we developed a hyaluronic acid-curcumin (HA-CUR) polymeric prodrug targeting to epithelial cells and then relieving oxidative stress damages. The water solubility of HA-CUR was significantly enhanced and approximately 27-fold higher than that of CUR. Cellular uptake test showed HA-CUR was preferably internalized by H2O2-pretreated tubular epithelial (HK-2) cells compared with free CUR benefiting from the specific binding between HA and CD44 receptors. Biodistribution results further demonstrated the increased accumulation of HA-CUR in kidneys with 13.9-fold higher than that of free CUR. Pharmacodynamic studies indicated HA-CUR effectively ameliorated AKI, and the exact mechanism was that HA-CUR protected renal tubule epithelial cells from oxidative stress damage via inhibiting PtdIns3K-AKT-mTOR signaling pathway. Taken together, this study provides a new therapeutic strategy for the treatment of AKI based on the pathogenesis of the disease.