Targeting superoxide dismutase to renal proximal tubule cells attenuates vancomycin-induced nephrotoxicity in rats
Targeting superoxide dismutase to renal proximal tubule cells attenuates vancomycin-induced nephrotoxicity in rats
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DOI：
10.1080/1071576031000061002
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发表时间：
2003-01-01
影响因子：
3.3
通讯作者：
Kinoshita, H
中科院分区：
文献类型：
--
作者：
Nishino, Y;Takemura, S;Kinoshita, H
盐酸万古霉素（VCM）是一种糖肽类抗生素，对耐甲氧西林金黄色葡萄球菌（MRSA）具有广谱抗菌作用。由于已知其可诱导肾功能不全，因此其给药剂量和持续时间有限。此外，VCM引起肾功能不全的机制仍不清楚。为了评估自由基对VCM诱导的肾功能不全的参与，我们进行了分析与六亚甲基二胺结合的超氧化物歧化酶（AH-SOD），迅速积累在肾近端小管细胞，抑制肾脏的氧化损伤。雄性Wistar大鼠（体重200 - 210 g）腹腔注射200 mg/kg VCM，每日两次，共7天。每次注射VCM前5min皮下注射AH-SOD 5mg/kg/d。VCM致肾损伤呈剂量依赖性。生化分析表明，血尿素氮和肌酐的血浆水平显着增加，在VCM治疗组的AH-SOD-reproditable机制。VCM同时引起增加8-OHdG水平和化学发光强度的自由基产生在肾脏中。组织学检查显示，VCM也引起了显着的破坏肾小球和近端小管坏死。AH-SOD可抑制肾脏的上述现象。这些结果表明，氧化应激可能是VCM诱导的肾毒性的发病机制的基础，并且将SOD和/或相关抗氧化剂靶向肾近端小管可能允许给予足以根除MRSA而不引起肾损伤的更高剂量的VCM。
Vancomycin hydrochloride (VCM), a glycopeptide antibiotic, has a broad spectrum against methicillin-resistant Staphylococcus aureus (MRSA). As it is known to induce renal dysfunction, the dose and the duration of its administration are limited. Moreover, the mechanism of VCM-induced renal dysfunction remains to be unclear. To evaluate the involvement of free radical on VCM-induced renal dysfunction, we carried out analysis with a hexamethylenediamine-conjugated superoxide dismutase (AH-SOD) which rapidly accumulates in renal proximal tubule cells and inhibits oxidative injury of the kidney. Male Wistar rats (weighing 200-210 g) were intraperitonealy administered with 200 mg/kg of VCM twice a day for 7 days. AH-SOD 5 mg/kg/day was subcutaneously injected 5 min before every VCM injection. VCM induced renal injury dose-dependently. Biochemical analyses revealed that plasma levels of blood urea nitrogen and creatinine significantly increased in the VCM-treated group by an AH-SOD-inhibitable mechanism. VCM simultaneously elicited an increase of 8-OHdG levels and chemiluminescence intensity of free radical generation in the kidney. Histological examination revealed that VCM also elicited a marked destruction of glomeruli and necrosis of proximal tubules. AH-SOD inhibited these phenomena in the kidney. These results suggested that oxidative stress might underlie the pathogenesis of VCM-induced nephrotoxicity and targeting SOD and/or related antioxidants to renal proximal tubules might permit the administration of higher doses of VCM sufficient for eradication of MRSA without causing renal injury.