Abstract

Tempol (4-hydroxy tempo), a pleiotropic antioxidant is reported to afford protection against cisplatin (CP)-induced nephrotoxicity. However, molecular mechanisms of action of tempol in improving the renal function in CP-induced nephrotoxicity are not fully understood. We investigated the attenuating effect of tempol against CP-induced alterations in kidney injury molecule-1 (KIM-1) and aquaporins (AQPs) in mice. Tempol (100 mg/kg, po) pretreatment with CP (20 mg/kg ip) showed restoration in renal function markers including electrolytes. CP treatment upregulated mRNA expression of KIM-1 and downregulated AQP and arginine vasopressin (AVP) expression which was attenuated by tempol. Immunoblotting analysis revealed that CP-induced alterations in KIM-1 and AQP expression were restored by tempol. Immunofluorocense study also showed restorative effect of tempol on the expression of AQP2 in CP-treated mice. In conclusion, this study provides experimental evidence that tempol resolved urinary concentration defect by the restoration of AQP, AVP and KIM-1 levels indicating a potential use of tempol in ameliorating the AKI in cancer patients under the treatment with CP.

摘要

据报道，Tempol (4-hydroxy tempo) 是一种多效抗氧化剂，可防止顺铂 (CP) 诱导的肾毒性。然而，tempol 在改善 CP 诱导的肾毒性中肾功能的分子机制尚不完全清楚。我们研究了 tempol 对 CP 诱导的小鼠肾损伤分子 1 (KIM-1) 和水通道蛋白 (AQP) 改变的减弱作用。Tempol (100 mg/kg, po ) 预处理 CP (20 mg/kg ip) 显示肾功能标志物（包括电解质）的恢复。CP 处理上调 KIM-1 的 mRNA 表达，下调 AQP 和精氨酸加压素 (AVP) 的表达，这些表达被 tempol 减弱。免疫印迹分析显示 CP 诱导的 KIM-1 和 AQP 表达改变通过 tempol 恢复。免疫荧光研究还显示 tempol 对 CP 治疗小鼠中 AQP2 表达的恢复作用。总之，这项研究提供了实验证据，表明 tempol 通过恢复 AQP、AVP 和 KIM-1 水平解决了尿浓度缺陷，表明 tempol 在改善 CP 治疗的癌症患者 AKI 中的潜在用途。