Wang Xinhui, Grunz-Borgmann Elizabeth A, Parrish Alan R
Department of Medical Pharmacology and Physiology, School of Medicine, University, of Missouri, Columbia, Missouri 65212.
Department of Medical Pharmacology and Physiology, School of Medicine, University, of Missouri, Columbia, Missouri 65212
Toxicol Sci. 2014 Sep;141(1):254-62. doi: 10.1093/toxsci/kfu130. Epub 2014 Jun 27.
Cisplatin is one of the most potent and widely used antitumor drugs. However, the use of cisplatin is limited by its side effect, nephrotoxicity. Evidence has shown an increased incidence and severity of acute kidney injury (AKI) in the elderly. Previous studies from our laboratory demonstrate a decrease in α(E)-catenin expression in aged kidney. In this study, we investigated whether the loss of α(E)-catenin may increase cisplatin nephrotoxicity. To study the effects of reduced α(E)-catenin, a cell line with stable knockdown of α(E)-catenin (C2 cells) was used; NT3 is nontargeted control. C2 cells exhibited a significant loss of viability as determined by MTT assay compared with NT3 cells after cisplatin challenge, but showed no difference in lactate dehydrogenase (LDH) leakage. Increased caspase 3/7 activation and PARP cleavage was observed in C2 cells after cisplatin treatment. Z-VAD, a pan-caspase inhibitor, abolished the difference in susceptibility between NT3 and C2 cells. Interestingly, the expression of α(E)-catenin was further decreased after cisplatin treatment. Furthermore, in vivo data demonstrated a significant increase in serum creatinine at 72 h after a single dose of cisplatin in 24-month-old rats, but not in 4-month-old rats. Increased expression of KIM-1 and in situ apoptosis were also detected in aged kidney after cisplatin challenge. Taken together, these data suggest that loss of α(E)-catenin increases apoptosis of tubular epithelial cells which may contribute to the increased nephrotoxicity induced by cisplatin in aged kidney.
顺铂是最有效的且广泛应用的抗肿瘤药物之一。然而，顺铂的使用受到其副作用——肾毒性的限制。有证据表明老年人急性肾损伤（AKI）的发生率和严重程度有所增加。我们实验室之前的研究表明，老年肾脏中α（E）-连环蛋白的表达会减少。在本研究中，我们调查了α（E）-连环蛋白的缺失是否会增加顺铂的肾毒性。为了研究α（E）-连环蛋白减少的影响，我们使用了一种α（E）-连环蛋白稳定敲低的细胞系（C2细胞）；NT3是未靶向的对照。与顺铂攻击后的NT3细胞相比，通过MTT试验测定，C2细胞的活力显著丧失，但乳酸脱氢酶（LDH）泄漏没有差异。顺铂处理后，在C2细胞中观察到半胱天冬酶3/7激活增加和聚（ADP-核糖）聚合酶（PARP）裂解。泛半胱天冬酶抑制剂Z-VAD消除了NT3和C2细胞之间易感性的差异。有趣的是，顺铂处理后α（E）-连环蛋白的表达进一步降低。此外，体内数据表明，单剂量顺铂给药72小时后，24月龄大鼠的血清肌酐显著增加，而4月龄大鼠则没有。顺铂攻击后，老年肾脏中也检测到肾损伤分子-1（KIM-1）表达增加和原位凋亡。综上所述，这些数据表明α（E）-连环蛋白的缺失会增加肾小管上皮细胞的凋亡，这可能导致老年肾脏中顺铂诱导的肾毒性增加。
