Park Jiyoung, Sim Juhyun, Yi Ho Jin, Rhee Sue Goo, Woo Hyun Ae
College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 120-750, South Korea; Fluorescence Core Imaging Center, Department of Life Science, Ewha Womans University, Seoul, South Korea.
College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 120-750, South Korea; National Forensic Service, 26460, 10 Ipchun-ro, Wonju, Gangwon-do, South Korea.
Free Radic Biol Med. 2024 Nov 20;225:236-246. doi: 10.1016/j.freeradbiomed.2024.09.049. Epub 2024 Oct 2.
In this study, we investigated the potential role of PrxI in cis-diamminedichloroplatinum (cisplatin)-induced renal damage in mice. The anticancer drug cisplatin is a chemotherapeutic agent that is widely used to treat solid tumors. Cisplatin-induced nephrotoxicity is a serious dose-limiting side effect, primarily caused by oxidative stress. The oxidative stress further damages DNA, membranes, and mitochondria, and increases endoplasmic reticulum (ER) stress. Cisplatin produces reactive oxygen species (ROS) through Cytochrome P450 2E1 (CYP2E1) and localizes to the surface of the ER, where CYP2E1 is located. Among the six Prx isoforms, Prx I was selectively degraded in cisplatin-treated kidneys during severe renal function damage. Prx I degradation is blocked in mouse proximal tubular cells treated with 3-methyladenine, an autophagy inhibitor, and in MEF lacking ATG7. Moreover, increased ROS levels on the ER surface due to CYP2E1 overexpression further accelerated Prx I degradation. These results suggest that Prx I degradation is largely mediated through autophagy, which is promoted by cisplatin-induced ER stress. Ablation of Prx I exacerbated cisplatin-induced nephrotoxicity and significantly increased the abundance of oxidative stress, ER stress, and inflammatory markers in the kidney, indicating that Prx I plays a protective role against cisplatin-induced nephrotoxicity.
在本研究中，我们调查了过氧化物还原酶I（PrxI）在顺二氯二氨铂（顺铂）诱导的小鼠肾损伤中的潜在作用。抗癌药物顺铂是一种广泛用于治疗实体瘤的化疗药物。顺铂诱导的肾毒性是一种严重的剂量限制性副作用，主要由氧化应激引起。氧化应激进一步损害DNA、细胞膜和线粒体，并增加内质网（ER）应激。顺铂通过细胞色素P450 2E1（CYP2E1）产生活性氧（ROS），并定位于ER表面，CYP2E1也位于该表面。在六种Prx亚型中，在严重肾功能损害期间，Prx I在顺铂处理的肾脏中被选择性降解。在用自噬抑制剂3-甲基腺嘌呤处理的小鼠近端肾小管细胞以及缺乏ATG7的小鼠胚胎成纤维细胞（MEF）中，Prx I的降解被阻断。此外，由于CYP2E1过表达导致ER表面ROS水平升高，进一步加速了Prx I的降解。这些结果表明，Prx I的降解主要通过自噬介导，而自噬由顺铂诱导的ER应激所促进。敲除Prx I会加剧顺铂诱导的肾毒性，并显著增加肾脏中氧化应激、ER应激和炎症标志物的丰度，表明Prx I对顺铂诱导的肾毒性起保护作用。
