Meclofenamate elicits a nephropreventing effect in a rat model of ischemic acute kidney injury by suppressing indoxyl sulfate production and restoring renal organic anion transporters.
Meclofenamate elicits a nephropreventing effect in a rat model of ischemic acute kidney injury by suppressing indoxyl sulfate production and restoring renal organic anion transporters.
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DOI：
10.2147/dddt.s67456
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Saito H
中科院分区：
文献类型：
--
作者：
Saigo C;Nomura Y;Yamamoto Y;Sagata M;Matsunaga R;Jono H;Nishi K;Saito H
硫酸吲哚酚（IS）是一种公认的低分子量尿毒症毒素，在肾功能正常的情况下通过尿液排泄，但在急性肾损伤和慢性肾脏疾病的肾功能不全期间保留在循环和组织中。IS是肾脏和心血管系统中最有效的氧化应激诱导剂之一，在肝脏中由吲哚通过细胞色素P450介导的羟基化为吲哚酚，然后通过磺基转移酶介导的硫酸盐结合酶促产生。我们使用大鼠肝脏S9组分来鉴定IS产生的抑制剂。在测试了包括植物化学多酚在内的几种化合物后，我们确定了美克洛酯是IS产生的有效抑制剂，表观IC 50值为1.34 μM。手术后48小时，大鼠肾脏缺血/再灌注（I/R）导致血清IS浓度显着升高。然而，静脉注射甲氨蝶呤（10 mg/kg）可显著抑制IS血清水平的升高。此外，肾脏和肝脏中的IS浓度通过肾脏I/R治疗显著升高，但这种增加被甲氨蝶呤阻断。肾I/R治疗后，大鼠血清肌酐和血尿素氮显著升高，但给予甲氨蝶呤后，这些升高显著恢复。I/R处理可下调肾基底外侧膜定位有机阴离子转运体rOAT 1和rOAT 3的表达。然而，rOAT 1和rOAT 3的表达在给予甲氨蝶呤后恢复，这与抑制I/R诱发的前列腺素E2升高有关。我们的研究结果表明，甲氨蝶呤抑制肝磺基转移酶介导的生产IS，从而抑制血清和肾脏积累的IS。甲氨蝶呤还可防止rOAT 1和rOAT 3表达的前列腺素E2依赖性下调。总之，发现甲氨蝶呤在缺血性急性肾损伤中具有肾脏预防作用。
Indoxyl sulfate (IS), a putative low-molecular weight uremic toxin, is excreted in the urine under normal kidney function, but is retained in the circulation and tissues during renal dysfunction in acute kidney injury and chronic kidney disease. IS, which is one of the most potent inducers of oxidative stress in the kidney and cardiovascular system, is enzymatically produced in the liver from indole by cytochrome P450-mediated hydroxylation to indoxyl, followed by sulfotransferase-mediated sulfate conjugation. We used rat liver S9 fraction to identify inhibitors of IS production. After testing several compounds, including phytochemical polyphenols, we identified meclofenamate as a potent inhibitor of IS production with an apparent IC50 value of 1.34 μM. Ischemia/reperfusion (I/R) of rat kidney caused a marked elevation in the serum IS concentration 48 hours after surgery. However, intravenous administration of meclofenamate (10 mg/kg) significantly suppressed this increase in the serum level of IS. Moreover, IS concentrations in both kidney and liver were dramatically elevated by renal I/R treatment, but this increase was blocked by meclofenamate. Serum creatinine and blood urea nitrogen were markedly elevated in rats after renal I/R treatment, but these increases were significantly restored by administration of meclofenamate. Renal expression of both basolateral membrane-localized organic anion transporters rOAT1 and rOAT3 was downregulated by I/R treatment. However, expression of rOAT1 and rOAT3 recovered after administration of meclofenamate, which is associated with the inhibition of I/R-evoked elevation of prostaglandin E2. Our results suggest that meclofenamate inhibits hepatic sulfotransferase-mediated production of IS, thereby suppressing serum and renal accumulation of IS. Meclofenamate also prevents the prostaglandin E2-dependent downregulation of rOAT1 and rOAT3 expression. In conclusion, meclofenamate was found to elicit a nephropreventive effect in ischemic acute kidney injury.