Comparison of kidney injury molecule-1 and other nephrotoxicity biomarkers in urine and kidney following acute exposure to gentamicin, mercury, and chromium
Comparison of kidney injury molecule-1 and other nephrotoxicity biomarkers in urine and kidney following acute exposure to gentamicin, mercury, and chromium
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DOI：
10.1093/toxsci/kfm260
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发表时间：
2008-01-01
影响因子：
3.8
通讯作者：
Goering, Peter L.
中科院分区：
文献类型：
--
作者：
Zhou, Yuzhao;Vaidya, Vishal S.;Goering, Peter L.
需要敏感的生物标志物来在最早阶段检测肾损伤。本研究的目的是确定与传统使用的生物标志物相比，尿中肾损伤分子-1（Kim-1）蛋白胞外域的出现和肾组织中肾损伤分子-1/甲型肝炎病毒细胞受体-1（Kim-1/Havcr 1）基因的表达是否更能预测暴露于肾毒物后的肾损伤。给雄性Sprague-Dawley大鼠注射一系列剂量的庆大霉素、汞（Hg; HgCl 2）或铬（Cr; K2 Cr2 O 7）。结果显示，与血尿素氮（BUN）、血清肌酐和尿N-乙酰-β-D-氨基葡萄糖苷酶（NAG）相比，尿Kim-1和肾Kim-1/Havcr 1基因表达的增加与肾组织病理学的严重程度相关，并且在较低剂量的肾毒物中检测到。在一项时程研究中，暴露于庆大霉素（100 mg/kg）、Hg（0.25 mg/kg）或Cr（5 mg/kg）后24 h内，尿Kim-1升高，并在72 h内保持升高。NAG反应具有肾毒性依赖性，早期（庆大霉素）、晚期（Cr）或无变化（Hg）升高。在72小时，治疗后的任何三个肾毒物，有增加的Kim-1免疫反应性和坏死，涉及类似的近端小管的50%;然而，只有尿Kim-1显着增加，而BUN，血清肌酐，NAG与对照组没有差异。在用肝毒性半乳糖胺（1.1 mg/kg）处理的大鼠中，血清丙氨酸氨基转移酶升高，但未观察到尿Kim-1升高。尿Kim-1和肾脏Kim-1/Havcr 1表达似乎是敏感的和组织特异性的生物标志物，将改善暴露于肾毒性化学品和药物后早期急性肾损伤的检测。
Sensitive biomarkers are needed to detect kidney injury at the earliest stages. The objective of this study was to determine whether the appearance of kidney injury molecule-1 (Kim-1) protein ectodomain in urine and kidney injury molecule-1/ hepatitis A viral cellular receptor-1 (Kim-1/Havcr1) gene expression in kidney tissue may be more predictive of renal injury after exposure to nephrotoxicants when compared to traditionally used biomarkers. Male Sprague-Dawley rats were injected with a range of doses of gentamicin, mercury (Hg; HgCl2), or chromium (Cr; K2Cr2O7). The results showed that increases in urinary Kim-1 and kidney Kim-1/Havcr1 gene expression paralleled the degree of severity of renal histopathology and were detected at lower doses of nephrotoxicants when compared to blood urea nitrogen (BUN), serum creatinine, and urinary N-acetyl-beta-D-glucosaminidase (NAG). In a time course study, urinary Kim-1 was elevated within 24 h after exposure to gentamicin (100 mg/kg), Hg (0.25 mg/kg), or Cr (5 mg/kg) and remained elevated through 72 h. NAG responses were nephrotoxicant dependent with elevations occurring early (gentamicin), late (Cr), or no change (Hg). At 72 h, after treatment with any of the three nephrotoxicants, there was increased Kim-1 immunoreactivity and necrosis involving similar to 50% of the proximal tubules; however, only urinary Kim-1 was significantly increased, while BUN, serum creatinine, and NAG were not different from controls. In rats treated with the hepatotoxicant galactosamine (1.1 mg/kg), serum alanine aminotransferase was increased, but no increase in urinary Kim-1 was observed. Urinary Kim-1 and kidney Kim-1/Havcr1 expression appear to be sensitive and tissue-specific biomarkers that will improve detection of early acute kidney injury following exposure to nephrotoxic chemicals and drugs.