Departamento de Biofísica, Universidade Federal de São Paulo, São Paulo 04039032, Brazil.
Departamento de Medicina, Disciplina de Nefrologia, Universidade Federal de São Paulo, São Paulo 04039032, Brazil.
Int J Mol Sci. 2020 Oct 8;21(19):7416. doi: 10.3390/ijms21197416.
Cisplatin is a chemotherapy drug widely used in the treatment of solid tumors. However, nephrotoxicity has been reported in about one-third of patients undergoing cisplatin therapy. Proximal tubules are the main target of cisplatin toxicity and cellular uptake; elimination of this drug can modulate renal damage. Organic transporters play an important role in the transport of cisplatin into the kidney and organic cations transporter 2 (OCT-2) has been shown to be one of the most important transporters to play this role. On the other hand, multidrug and toxin extrusion 1 (MATE-1) transporter is the main protein that mediates the extrusion of cisplatin into the urine. Cisplatin nephrotoxicity has been shown to be enhanced by increased OCT-2 and/or reduced MATE-1 activity. Peroxisome proliferator-activated receptor alpha (PPAR-α) is the transcription factor which controls lipid metabolism and glucose homeostasis; it is highly expressed in the kidneys and interacts with both MATE-1 and OCT-2. Considering the above, we treated wild-type and PPAR-α knockout mice with cisplatin in order to evaluate the severity of nephrotoxicity. Cisplatin induced renal dysfunction, renal inflammation, apoptosis and tubular injury in wild-type mice, whereas PPAR-α deletion protected against these alterations. Moreover, we observed that cisplatin induced down-regulation of organic transporters MATE-1 and OCT-2 and that PPAR-α deletion restored the expression of these transporters. In addition, PPAR-α knockout mice at basal state showed increased MATE-1 expression and reduced OCT-2 levels. Here, we show for the first time that PPAR-α deletion protects against cisplatin nephrotoxicity and that this protection is via modulation of the organic transporters MATE-1 and OCT-2.
顺铂是一种广泛用于治疗实体瘤的化疗药物。然而，大约三分之一接受顺铂治疗的患者会出现肾毒性。顺铂毒性的主要靶器官是近端肾小管，细胞摄取；这种药物的消除可以调节肾损伤。有机转运体在顺铂进入肾脏的转运中起着重要作用，有机阳离子转运体 2（OCT-2）已被证明是发挥这一作用的最重要转运体之一。另一方面，多药和毒素外排 1（MATE-1）转运蛋白是介导顺铂排入尿液的主要蛋白。顺铂肾毒性已被证明通过增加 OCT-2 和/或减少 MATE-1 活性而增强。过氧化物酶体增殖物激活受体 α（PPAR-α）是控制脂质代谢和葡萄糖稳态的转录因子；它在肾脏中高度表达，并与 MATE-1 和 OCT-2 相互作用。考虑到上述情况，我们用顺铂治疗野生型和 PPAR-α 敲除小鼠，以评估肾毒性的严重程度。顺铂诱导野生型小鼠肾功能障碍、肾炎症、细胞凋亡和肾小管损伤，而 PPAR-α 缺失可预防这些改变。此外，我们观察到顺铂诱导有机转运体 MATE-1 和 OCT-2 的下调，而 PPAR-α 缺失恢复了这些转运体的表达。此外，PPAR-α 敲除小鼠在基础状态下表现出 MATE-1 表达增加和 OCT-2 水平降低。在这里，我们首次表明 PPAR-α 缺失可预防顺铂肾毒性，而这种保护作用是通过调节有机转运体 MATE-1 和 OCT-2 实现的。
