Acute kidney injury model established by systemic glutathione depletion in mice
Acute kidney injury model established by systemic glutathione depletion in mice
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DOI：
10.1002/jat.3780
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发表时间：
2019-06
影响因子：
3.3
通讯作者：
Akiko Matsubara;Shingo Oda;Ru Jia;T. Yokoi
中科院分区：
文献类型：
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作者：
Akiko Matsubara;Shingo Oda;Ru Jia;T. Yokoi
谷胱甘肽（GSH）是研究最广泛的三肽之一。GSH在氧化还原信号传导、外源物质解毒和抗氧化防御中的作用已被研究。最近，通过抗菌药物和他汀类药物联合给药，在L-丁硫氨酸-（S，R）-亚砜亚胺（BSO;一种GSH合成抑制剂）处理的正常小鼠中建立了药物诱导的横纹肌溶解症小鼠模型。在这些模型中，在仅BSO处理的小鼠中观察到轻度肾损伤。因此，在本研究中，我们研究了GSH耗竭小鼠的肾损伤。将BSO腹腔内给予正常小鼠，每天两次，持续7天。肌酸磷酸激酶在第8天达到最高值（351 487 ± 53 815 U/L），天冬氨酸转氨酶在第6天达到最高值。观察到血尿素氮、血浆肌酐、尿肾损伤分子-1和尿肌酐水平升高。观察到肾脂质运载蛋白2/中性粒细胞明胶酶相关脂质运载蛋白的mRNA表达水平增加。从BSO给药第5天开始，骨骼肌出现变性和坏死，血液（347 - 203 925 ng/mL）和尿液（2.5 - 68 583 ng/mL）中肌红蛋白（Mb）浓度较高，个体间变异性较大。对肾小管和肾管型中的Mb染色区域进行组织学观察。在本研究中，GSH耗竭处理由于受损骨骼肌释放Mb而建立了急性肾损伤小鼠模型。该小鼠模型可用于预测非临床药物开发中潜在的急性肾损伤风险。
Glutathione (GSH) is one of the most extensively studied tripeptides. The roles for GSH in redox signaling, detoxification of xenobiotics and antioxidant defense have been investigated. A drug‐induced rhabdomyolysis mouse model was recently established in L‐buthionine‐(S,R)‐sulfoximine (BSO; a GSH synthesis inhibitor)‐treated normal mice by co‐administration of antibacterial drug and statin. In these models, mild kidney injury was observed in the BSO only‐treated mice. Therefore, in this study, we studied kidney injury in the GSH‐depleted mouse. BSO was intraperitoneally administered twice a day for 7 days to normal mice. The maximum level of plasma creatine phosphokinase (351 487 ± 53 815 U/L) was shown on day 8, and that of aspartate aminotransferase was shown on day 6. Increased levels of blood urea nitrogen, plasma creatinine, urinary kidney injury molecule‐1 and urinary creatinine were observed. An increase of mRNA expression level of renal lipocalin 2/neutrophil gelatinase‐associated lipocalin was observed. Degeneration and necrosis in the skeletal muscle and high concentrations of myoglobin (Mb) in blood (347‐203 925 ng/mL) and urine (2.5‐68 583 ng/mL) with large interindividual variability were shown from day 5 of BSO administration. Mb‐stained regions in the renal tubule and renal cast were histologically observed. In this study, the GSH‐depletion treatment established an acute kidney injury mouse model due to Mb release from the damaged skeletal muscle. This mouse model would be useful for predicting potential acute kidney injury risks in non‐clinical drug development.