Division of Nephrology, Department of Medicine, UNIFESP/EPM, São Paulo, Brazil.
Toxicol Appl Pharmacol. 2011 May 15;253(1):1-6. doi: 10.1016/j.taap.2011.02.022. Epub 2011 Mar 22.
Nephrotoxicity is the main side effect of gentamicin (GENTA). Preconditioning (PC) refers to a situation in which an organ subjected to an injury responds less intensely when exposed to another injury. The aim of this study was to evaluate the effect of PC with GENTA on nephrotoxic acute kidney injury (AKI). GENTA group rats were injected daily with GENTA (40 mg/kg/BW) for 10 days. PC animals were injected with GENTA for 3 days (40 mg/kg/BW/daily) and, after one rest week, were injected daily with GENTA for 10 days. Animals of the L-NAME and DICLO groups were preconditioned for 3 days and then received daily injections of GENTA for 10 days; they were concomitantly treated with L-NAME (10 mg/kg/BW) and diclofenac (DICLO, 5 mg/kg/BW) for 13 days. Blood and urine were collected for measurement of serum creatinine, urea, urine sodium, protein, hydroperoxides, lipid peroxidation and nitric oxide (NO). The animals were killed; kidneys were removed for histology and immunohistochemistry for apoptosis and cell proliferation. GENTA group rats showed an increase in plasma creatinine, urea, urine sodium, hydroperoxides, lipid peroxidation, proteinuria, necrosis and apoptosis, characterizing nephrotoxic AKI. PC animals showed a decrease in these parameters and increased proliferation. The blockade of NO synthesis by L-NAME potentiated the protective effect, suggesting that NO contributed to the injury caused by GENTA. The blockade of prostaglandin synthesis with DICLO increased serum and urinary parameters, blunting the protective effect of PC. Our data suggest that PC could be a useful tool to protect against nephrotoxic AKI.
肾毒性是庆大霉素（GENTA）的主要副作用。预处理（PC）是指器官受到损伤后，再次暴露于另一种损伤时反应较弱的情况。本研究旨在评估 GENTA 预处理对肾毒性急性肾损伤（AKI）的影响。GENTA 组大鼠每天注射 GENTA（40mg/kg/BW）10 天。PC 动物连续 3 天（40mg/kg/BW/天）注射 GENTA，休息一周后，每天注射 GENTA 10 天。L-NAME 和 DICLO 组动物预处理 3 天，然后每天注射 GENTA 10 天；同时给予 L-NAME（10mg/kg/BW）和双氯芬酸（DICLO，5mg/kg/BW）治疗 13 天。收集血液和尿液，用于测量血清肌酐、尿素、尿钠、蛋白、羟自由基、脂质过氧化和一氧化氮（NO）。处死动物，取出肾脏进行组织学和凋亡及细胞增殖的免疫组织化学检查。GENTA 组大鼠血浆肌酐、尿素、尿钠、羟自由基、脂质过氧化、蛋白尿、坏死和凋亡增加，表现为肾毒性 AKI。PC 动物这些参数下降，增殖增加。用 L-NAME 阻断 NO 合成增强了保护作用，表明 NO 导致了 GENTA 引起的损伤。用 DICLO 阻断前列腺素合成增加了血清和尿参数，削弱了 PC 的保护作用。我们的数据表明，PC 可能是预防肾毒性 AKI 的有用工具。
