Department of Clinical Pharmaceutical Sciences, Kumamoto University Graduate School of Pharmaceutical Sciences, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan.
Clin Exp Nephrol. 2011 Dec;15(6):820-30. doi: 10.1007/s10157-011-0524-z. Epub 2011 Aug 23.
Polyphenols such as quercetin have been reported to prevent cisplatin-induced acute kidney injury (AKI). Indoxyl sulfate (IS), a uremic toxin generated in the liver, is increased in cisplatin AKI. The present study examined the effect of phytochemical polyphenols on serum and renal accumulations of IS in association with cisplatin AKI.
Sprague-Dawley rats were treated with cisplatin (10 mg/kg body weight) by intraperitoneal injection. Polyphenols were orally administered at -24, -1, 24 and 48 h before or after cisplatin injection. Serum levels of IS, cisplatin, serum creatinine (SCr), blood urea nitrogen (BUN) and electrolytes were measured. By using an in vitro assay system with rat liver S9 fraction, the inhibitory potencies of several compounds on IS production were determined.
Injection of cisplatin in rats markedly elevated the SCr and BUN levels, which were accompanied by tubular injuries and the expression of kidney injury molecule-1 (Kim-1). By contrast, quercetin significantly suppressed the SCr and BUN levels in the cisplatin-treated rats and protected them against renal injury with the decreased expression of Kim-1. Quercetin had no effect on serum and renal levels of cisplatin. In addition, quercetin had no effect on cisplatin-induced renal accumulation of malondialdehyde. IS concentrations in serum, kidney, liver, intestine and lung were markedly elevated by cisplatin treatment, whereas quercetin suppressed the serum and tissue IS levels. An in vitro kinetic assay revealed that quercetin displayed a potent inhibitory effect on hepatic production of IS.
Inhibition of IS accumulation by oral administration of quercetin alleviates cisplatin-induced AKI.
已有研究报道，多酚类物质如槲皮素可预防顺铂诱导的急性肾损伤（AKI）。硫酸吲哚酚（IS）是一种在肝脏中生成的尿毒症毒素，在顺铂性 AKI 中会增加。本研究检测了植物化学多酚类物质对与顺铂性 AKI 相关的血清和肾内 IS 蓄积的影响。
通过腹腔注射顺铂（10mg/kg 体重）对 Sprague-Dawley 大鼠进行处理。多酚类物质在顺铂注射前 24 小时、前 1 小时、24 小时和 48 小时以及注射后进行口服给药。测定血清中 IS、顺铂、血清肌酐（SCr）、血尿素氮（BUN）和电解质的水平。使用大鼠肝 S9 级分的体外测定系统，测定了几种化合物对 IS 生成的抑制能力。
顺铂注射到大鼠体内后，明显升高了 SCr 和 BUN 水平，同时伴有肾小管损伤和肾损伤分子-1（Kim-1）的表达。相比之下，槲皮素显著抑制了顺铂处理大鼠的 SCr 和 BUN 水平，并通过降低 Kim-1 的表达保护它们免受肾损伤。槲皮素对血清和肾内顺铂水平没有影响。此外，槲皮素对顺铂诱导的肾内丙二醛蓄积没有影响。IS 浓度在血清、肾脏、肝脏、肠道和肺中明显因顺铂处理而升高，而槲皮素抑制了血清和组织中的 IS 水平。体外动力学测定显示，槲皮素对肝脏 IS 生成具有很强的抑制作用。
口服给予槲皮素抑制 IS 蓄积可减轻顺铂诱导的 AKI。
