Xi Yang ,Zhiguang Li ,Zhenqiang Su ,Kelly Davis ,Tao Chen ,Donna L Mendrick ,William Salminen *
Several recent studies measured elevated levels of circulating plasma microRNAs (miRNAs) after toxicant-induced liver injury, most likely due to leakage from damaged hepatocytes. miRNAs have also been detected in urine with some of them being derived from organs outside of the urinary system, opening up their potential use as noninvasive biomarkers of disease or injury. Despite this potential, changes in urine miRNA profiles have not been investigated as biomarkers for drug-induced liver injury. In this study, urine miRNA profiles were assessed from rats treated with a single oral dose of acetaminophen (APAP: 100 or 1250 mg/kg). The low dose did not cause any clinical pathology or histopathological changes indicative of liver injury. In contrast, the high dose increased clinical pathology and histopathological indices of liver injury at 24 hours; however, there was a high inter-animal variability in these endpoints. No evidence of kidney injury was noted at either APAP dose. Urinary miRNA levels correlated best with the degree of liver centrilobular glycogen depletion. In contrast to the high inter-animal variability noted for serum alanine and aspartate aminotransferases and centrilobular liver necrosis, urinary miRNA levels were consistently elevated in all high dose animals. Alterations in the urinary miRNA profiles were also noted in the low dose animals, albeit fewer in number. These results suggest that specific miRNAs in the urine could reflect the severity of APAP-induced liver injury and therefore have the potential to be used as noninvasive preclinical and clinical biomarkers.
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