Centre for Biomedical Investigations, IVIC-Zulia, Maracaibo, Venezuela.
Basic Clin Pharmacol Toxicol. 2009 Dec;105(6):416-24. doi: 10.1111/j.1742-7843.2009.00466.x. Epub 2009 Oct 12.
In this work, we aimed to study the effect of uric acid on gentamicin-induced nephrotoxicity. Male Sprague-Dawley rats were assigned to one of six groups (six rats each) which received intraperitoneal injections for 9 days: (S) saline; (UA) Uric acid alone; (G) Gentamicin alone; (G + UA) Gentamicin + uric acid; (G rec) Gentamicin recovery and (G + UA rec) Gentamicin + uric acid recovery. In (G rec) and (G + UA rec), rats recovered for 7 days after the last injection. Urine and blood samples were taken on day 0 and at the end of every stage. Kidneys were harvested for histological scoring, determination of renal malondialdehyde (MDA), zymography and western blots for matrix metalloprotease (MMP)-2 and MMP-9. Uric acid alone did not provoke changes in biochemical and histological parameters when compared to controls. Gentamicin alone increased significantly plasma creatinine and blood urea nitrogen and caused a moderate histological damage. When combined with uric acid, these conditions worsened. MMP-9 activity and expression was decreased in rats from group G + UA as compared with rats from group G, while activity of MMP-2 was similarly increased in both groups when compared to controls. The increase in renal MDA induced by gentamicin was not altered when it was combined with uric acid. During the recovery stage, all biochemical parameters returned to normal levels, though a trend for delay of tubular damage recovery was observed in group G + UA rec when compared with group G rec. The results indicate that uric acid worsens gentamicin-induced nephrotoxicity. The mechanism is likely to implicate down-regulation of MMP-9.
在这项工作中，我们旨在研究尿酸对庆大霉素诱导的肾毒性的影响。雄性 Sprague-Dawley 大鼠被分为六组（每组六只），每组大鼠连续 9 天接受腹腔注射：（S）生理盐水；（UA）尿酸单独；（G）庆大霉素单独；（G + UA）庆大霉素+尿酸；（G rec）庆大霉素恢复组和（G + UA rec）庆大霉素+尿酸恢复组。在（G rec）和（G + UA rec）组中，大鼠在最后一次注射后恢复 7 天。在第 0 天和每个阶段结束时采集尿液和血液样本。采集肾脏进行组织学评分、测定肾丙二醛（MDA）、酶谱分析和基质金属蛋白酶（MMP）-2 和 MMP-9 的 Western blot。尿酸单独与对照组相比，不会引起生化和组织学参数的变化。庆大霉素单独使用时，显著增加血浆肌酐和血尿素氮，并导致中度组织学损伤。当与尿酸联合使用时，这些情况会恶化。与 G 组相比，G + UA 组大鼠的 MMP-9 活性和表达降低，而两组大鼠的 MMP-2 活性均与对照组相比明显增加。庆大霉素诱导的肾 MDA 增加与尿酸联合使用时并未改变。在恢复阶段，所有生化参数均恢复正常水平，但与 G rec 组相比，G + UA rec 组肾小管损伤恢复的趋势延迟。结果表明，尿酸加重庆大霉素诱导的肾毒性。其机制可能涉及 MMP-9 的下调。
