Chen Qiuxia, Cui Yiyun, Ding Guixia, Jia Zhanjun, Zhang Yue, Zhang Aihua, Huang Songming
Department of Nephrology, Children's Hospital of Nanjing Medical UniversityNanjing 210008, Jiangsu Province, P. R. China.
Jiangsu Key Laboratory of PediatricsNanjing 210029, Jiangsu Province, P. R. China.
Am J Transl Res. 2017 May 15;9(5):2153-2162. eCollection 2017.
Toxin-induced nephrotoxicity is one of the major causes leading to the acute kidney injury (AKI). Among these nephrotoxic toxins, gentamicin can induce AKI with elusive mechanisms. Emerging evidence demonstrated that PEA3 (polyomavirus enhancer activator 3) contributed to the nephrogenesis, while its role in AKI remains unknown. Thus, this study was to investigate the role of PEA3 in gentamicin nephrotoxicity, as well as the underlying mechanisms. In rats, gentamicin treatment (200 mg/kg twice per day) for two days induced remarkable kidney injury with a peak damage on day 5 evaluated by the tubular injury score, proteinuria, and tubular injury markers of NGAL and KIM-1. In parallel with the tubular injury, PEA3 protein and mRNA expressions were significantly upregulated by gentamicin and peaked on day 5. To define the role of PEA3 in gentamicin nephrotoxicity, proximal tubule cells were transfected with PEA3 plasmid with or without gentamicin treatment (1 mg/ml). Notably, overexpression of PEA3 attenuated gentamicin-induced cell injury shown by the ameliorated cell apoptosis and NGAL and KIM-1 upregulation. Meantime, gentamicin caused severe mitochondrial dysfunction, which was largely normalized by PEA3 overexpression. In contrast, silencing PEA3 by a siRNA strategy further deteriorated gentamicin-induced cell apoptosis and mitochondrial dysfunction. In sum, PEA3 protected against gentamicin nephrotoxicity possibly via a mitochondrial mechanism.
毒素诱导的肾毒性是导致急性肾损伤（AKI）的主要原因之一。在这些肾毒性毒素中，庆大霉素可诱导AKI，但其机制尚不清楚。新出现的证据表明，PEA3（多瘤病毒增强子激活剂3）有助于肾发生，但其在AKI中的作用仍不清楚。因此，本研究旨在探讨PEA3在庆大霉素肾毒性中的作用及其潜在机制。在大鼠中，庆大霉素治疗（200mg/kg，每天两次）持续两天可诱导显著的肾损伤，在第5天通过肾小管损伤评分、蛋白尿以及NGAL和KIM-1的肾小管损伤标志物评估，损伤达到峰值。与肾小管损伤同时，庆大霉素显著上调PEA3蛋白和mRNA表达，并在第5天达到峰值。为了确定PEA3在庆大霉素肾毒性中的作用，对近端肾小管细胞转染PEA3质粒，同时进行或不进行庆大霉素处理（1mg/ml）。值得注意的是，PEA3过表达减轻了庆大霉素诱导的细胞损伤，表现为细胞凋亡改善以及NGAL和KIM-1上调减少。同时，庆大霉素导致严重的线粒体功能障碍，而PEA3过表达在很大程度上使其恢复正常。相反，通过小干扰RNA策略沉默PEA3会进一步恶化庆大霉素诱导的细胞凋亡和线粒体功能障碍。总之，PEA3可能通过线粒体机制保护细胞免受庆大霉素肾毒性的影响。
