PPAR-α Deletion Attenuates Cisplatin Nephrotoxicity by Modulating Renal Organic Transporters MATE-1 and OCT-2.
PPAR-α Deletion Attenuates Cisplatin Nephrotoxicity by Modulating Renal Organic Transporters MATE-1 and OCT-2.
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DOI：
10.3390/ijms21197416
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发表时间：
2020-10-08
影响因子：
5.6
通讯作者：
Estrela GR
中科院分区：
文献类型：
--
作者：
Freitas-Lima LC;Budu A;Arruda AC;Perilhão MS;Barrera-Chimal J;Araujo RC;Estrela GR
顺铂是一种广泛应用于实体瘤治疗的化疗药物。然而，约三分之一接受顺铂治疗的患者有肾毒性报道。近端小管是顺铂毒性和细胞摄取的主要目标；停用该药可调节肾损害。有机转运蛋白在顺铂进入肾脏的转运中起着重要作用，有机阳离子转运蛋白2 （OCT-2）已被证明是发挥这一作用的最重要的转运蛋白之一。另一方面，多药毒素挤压1 （MATE-1）转运蛋白是介导顺铂挤压入尿的主要蛋白。顺铂肾毒性已被证明会因OCT-2增加和/或MATE-1活性降低而增强。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。综上所述，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缺失对这些改变具有保护作用。此外，我们观察到顺铂诱导了有机转运体MATE-1和OCT-2的下调，PPAR-α的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，MATE-1表达增加，OCT-2水平降低。在这里，我们首次证明PPAR-α缺失可以防止顺铂肾毒性，并且这种保护是通过调节有机转运体MATE-1和OCT-2来实现的。
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.
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影响因子：
19.6
作者：
通讯作者：
--
影响因子：
6
作者：
Ciarimboli, Giuliano;Deuster, Dirk;Schlatter, Eberhard
通讯作者：
Schlatter, Eberhard
DOI：
10.1152/ajprenal.00206.2004
发表时间：
2004-11-01
影响因子：
4.2
作者：
Li, SY;Bhatt, R;Portilla, D
通讯作者：
Portilla, D
影响因子：
4
作者：
Estrela GR;Wasinski F;Batista RO;Hiyane MI;Felizardo RJ;Cunha F;de Almeida DC;Malheiros DM;Câmara NO;Barros CC;Bader M;Araujo RC
通讯作者：
Araujo RC
影响因子：
4.8
作者：
Ichimura, T;Bonventre, JV;Sanicola, M
通讯作者：
Sanicola, M