School of Pharmacy, College of Pharmacy, Taipei Medical University, No. 250, Wuxing Street, Taipei 11031, Taiwan, ROC.
Toxicol Lett. 2013 May 10;219(1):85-92. doi: 10.1016/j.toxlet.2013.01.024. Epub 2013 Feb 27.
In this study, we investigated the role of carbonyl stress in gentamicin (GM)-induced renal injury in rats. Carbonyl stress is represented by methylglyoxal (MGO) and its downstream advanced glycation end products, such as N(ɛ)-(carboxyethyl)lysine (CEL). GM (150mg/kg/day, i.p.) administration for 6 days significantly increased blood urea nitrogen (BUN) levels from 24.06±0.55 to 85.04±21.31mg/dL and decreased creatinine clearance rate (Ccr) from 10.68±0.76 to 2.53±1.11ml/min/kg B.W.; biopsy showed tubular injury. The kidney levels of MGO and CEL increased significantly from 9.56±1.94 to 79.13±17.96μg/g of protein and from 0.03±0.00 to 0.06±0.00μmol/μg of protein, respectively. Therefore, MGO and CEL appeared to be associated with GM-induced renal damage. Co-administration of metformin (50 or 100mg/kg/day) and GM for 13 days effectively reversed GM-induced renal damage. The kidney levels of MGO and CEL decreased significantly from 24.95±7.74 to 22.98±17.74μg/g of protein and from 0.04±0.01 to 0.03±0.01μmol/μg of protein (both vs. the GM group), respectively. The identification of this new pathway may help prevent GM-induced nephrotoxicity.
在这项研究中，我们研究了羰基应激在庆大霉素（GM）诱导的大鼠肾损伤中的作用。羰基应激由甲基乙二醛（MGO）及其下游的高级糖基化终产物表示，如 N（ɛ）-（羧乙基）赖氨酸（CEL）。GM（150mg/kg/天，腹腔注射）给药 6 天，使血尿素氮（BUN）水平从 24.06±0.55 增加到 85.04±21.31mg/dL，并使肌酐清除率（Ccr）从 10.68±0.76 降低到 2.53±1.11ml/min/kg B.W.；活检显示肾小管损伤。肾脏 MGO 和 CEL 的水平分别从 9.56±1.94 增加到 79.13±17.96μg/g 蛋白和从 0.03±0.00 增加到 0.06±0.00μmol/μg 蛋白，增加明显。因此，MGO 和 CEL 似乎与 GM 诱导的肾损伤有关。二甲双胍（50 或 100mg/kg/天）和 GM 联合给药 13 天可有效逆转 GM 诱导的肾损伤。肾脏 MGO 和 CEL 的水平分别从 24.95±7.74 降低到 22.98±17.74μg/g 蛋白和从 0.04±0.01 降低到 0.03±0.01μmol/μg 蛋白（与 GM 组相比），降低明显。这条新途径的鉴定可能有助于预防 GM 诱导的肾毒性。
