Reversal of cisplatin-induced carnitine deficiency and energy starvation by propionyl-L-carnitine in rat kidney tissues
Reversal of cisplatin-induced carnitine deficiency and energy starvation by propionyl-L-carnitine in rat kidney tissues
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DOI：
10.1111/j.1440-1681.2007.04714.x
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发表时间：
2007-12-01
影响因子：
2.9
通讯作者：
Sayed-Ahmed, Mohamed M.
中科院分区：
文献类型：
--
作者：
Aleisa, Abdulaziz M.;Al-Majed, Abdulhakeem A.;Sayed-Ahmed, Mohamed M.
1. 本研究探讨丙炔-左旋肉碱（PLC）是否能预防顺铂（CDDP）诱导的大鼠急性肾功能衰竭的发生。将40只成年雄性Wistar白化大鼠分为4组。第一组大鼠每天注射生理盐水（2.5 mL/kg, i.p.），连续10天；第二组大鼠注射PLC (250 mg/kg, i.p.)，连续10天。第三组动物在单次给药（7 mg/kg, i.p.）前后每天注射生理盐水，连续5天。第四组大鼠在单次给药CDDP （7 mg/kg, i.p.）前后连续5天联合给药PLC （250 mg/kg, i.p.）。CDDP治疗后第6天处死动物，分离血清和肾脏进行分析。3 .注射CDDP导致大鼠血清肌酐、血尿素氮（BUN）、硫代巴比托酸反应物质（TBARS）和总硝酸盐/亚硝酸盐（NOx）显著升高，肾组织中还原性谷胱甘肽（GSH）、总肉碱、ATP和ATP/ADP显著降低。PLC可显著减弱CDDP的肾毒性作用，表现为CDDP诱导的血清肌酐、BUN、TBARS和NOx的升高正常化，以及CDDP诱导的肾组织总肉毒碱、GSH、ATP和ATP/ADP的降低。cddp处理大鼠肾脏组织病理检查显示严重的肾毒性，50-75%的肾小球和肾小管出现大量退行性改变。有趣的是，对cddp治疗的大鼠给予PLC可显著改善肾小球和肾小管，其中不到25%的肾小球和肾小管出现局灶性坏死。本研究的数据表明，PLC阻止cddp诱导的急性肾损伤的发生，其机制至少部分与PLC增加细胞内肉碱含量的能力有关，从而改善线粒体氧化磷酸化和能量产生，以及其减少氧化应激的能力。这将为PLC在治疗与肉碱缺乏相关或继发于肉碱缺乏的肾脏疾病中的应用开辟新的前景。
1. The present study examined whether propionyl-L-carnitine (PLC) could prevent the development of cisplatin (CDDP)-induced acute renal failure in rats.2. Forty adult male Wistar albino rats were divided into four groups. Rats in the first group were injected daily with normal saline (2.5 mL/kg, i.p.) for 10 consecutive days, whereas the second group received PLC (250 mg/kg, i.p.) for 10 consecutive days. Animals in the third group were injected daily with normal saline for 5 consecutive days before and after a single dose of CDDP (7 mg/kg, i.p.). Rats in the fourth group received a combination of PLC (250 mg/kg, i.p.) for 5 consecutive days before and after a single dose of CDDP (7 mg/kg, i.p.). On Day 6 following CDDP treatment, animals were killed and serum and kidneys were isolated for analysis.3. Injection of CDDP resulted in a significant increase in serum creatinine, blood urea nitrogen (BUN), thiobarbituric acid-reactive substances (TBARS) and total nitrate/nitrite (NOx), as well as a significant decrease in reduced glutathione (GSH), total carnitine, ATP and ATP/ADP in kidney tissues.4. Administration of PLC significantly attenuated the nephrotoxic effects of CDDP, manifested as normalization of the CDDP-induced increase in serum creatinine, BUN, TBARS and NOx and the CDDP-induced decrease in total carnitine, GSH, ATP and ATP/ADP in kidney tissues.5. Histopathological examination of kidney tissues from CDDP-treated rats showed severe nephrotoxicity, in which 50-75% of glomeruli and renal tubules exhibited massive degenerative changes. Interestingly, administration of PLC to CDDP-treated rats resulted in a significant improvement in glomeruli and renal tubules, in which less than 25% of glomeruli and renal tubules exhibited focal necrosis.6. Data from the present study suggest that PLC prevents the development of CDDP-induced acute renal injury by a mechanism related, at least in part, to the ability of PLC to increase intracellular carnitine content, with a consequent improvement in mitochondrial oxidative phosphorylation and energy production, as well as its ability to decrease oxidative stress. This will open new perspectives for the use of PLC in the treatment of renal diseases associated with or secondary to carnitine deficiency.