Department of Nephrology, Central People's Hospital of Yichang, The First Clinical Medical College of Three Gorges University, Yichang, China.
Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, Georgia.
Am J Physiol Renal Physiol. 2020 Apr 1;318(4):F1041-F1052. doi: 10.1152/ajprenal.00512.2019. Epub 2020 Mar 9.
Cisplatin is a widely used chemotherapy drug with notorious nephrotoxicity. Na-glucose cotransporter 2 inhibitors are a class of novel antidiabetic agents that may have other effects in the kidneys besides blood glucose control. In the present study, we demonstrated that canagliflozin significantly attenuates cisplatin-induced nephropathy in C57BL/6 mice and suppresses cisplatin induced renal proximal tubular cell apoptosis in vitro. The protective effect of canagliflozin was associated with inhibition of p53, p38 and JNK activation. Mechanistically, canagliflozin partially reduced cisplatin uptake by kidney tissues in mice and renal tubular cells in culture. In addition, canagliflozin enhanced the activation of Akt and inhibited the mitochondrial pathway of apoptosis during cisplatin treatment. The protective effect of canagliflozin was diminished by the phosphatidylinositol 3-kinase/Akt inhibitor LY294002. Notably, canagliflozin did not affect the chemotherapeutic efficacy of cisplatin in A549 and HCT116 cancer cell lines. These results suggest a new application of canagliflozin for renoprotection in cisplatin chemotherapy. Canagliflozin may protect kidneys by reducing cisplatin uptake and activating cell survival pathways.
顺铂是一种广泛应用的化疗药物，具有明显的肾毒性。钠-葡萄糖共转运蛋白 2 抑制剂是一类新型的降糖药物，除了控制血糖外，它们在肾脏中可能还有其他作用。在本研究中，我们证实卡格列净可显著减轻 C57BL/6 小鼠顺铂诱导的肾损伤，并抑制顺铂诱导的体外肾小管细胞凋亡。卡格列净的保护作用与抑制 p53、p38 和 JNK 激活有关。在机制上，卡格列净部分减少了顺铂在小鼠肾脏组织和培养的肾小管细胞中的摄取。此外，卡格列净在顺铂处理过程中增强了 Akt 的激活并抑制了线粒体凋亡途径。PI3K/Akt 抑制剂 LY294002 减弱了卡格列净的保护作用。值得注意的是，卡格列净对 A549 和 HCT116 癌细胞系中顺铂的化疗疗效没有影响。这些结果表明卡格列净在顺铂化疗中具有新的肾脏保护作用。卡格列净可能通过减少顺铂摄取和激活细胞存活途径来保护肾脏。
