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Discovery of early urinary biomarkers in preclinical study of gentamicin-induced kidney injury and recovery in rats

机译：在庆大霉素诱导的大鼠肾脏损伤和恢复的临床前研究中发现早期尿液生物标志物

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摘要

LC/MS- and NMR-based global metabolomics analyses were utilized to study the changes in rat urine in response to gentamicin treatment. Sprague–Dawley rats were dosed with gentamicin sulfate at 0, 75, 150 or 300 mg/kg/day for one, two or three consecutive days. Four animals from each group were sacrificed to harvest kidney tissue and to collect urine on days 1, 2, 3, 7, 10, 15, 18, 22, 29, 36 and 44 for a total of 11 different time points. Both uni- and multivariate statistical analyses were employed to identify the significantly changed metabolites in urine at the different dose levels and time points. Increases and decreases in amino acids including tyrosine, valine and hydroxyproline reflected histopathology changes of kidney injury development and/or kidney injury recovery. Glucosuria was noted much earlier than changes in the classic kidney function biomarkers, blood urea nitrogen and serum creatinine. Dopamine-related compounds, homovanillic acid sulfate (HVA-SO4) and homoveratric acid sulfate (HVrA-SO4) were significantly increased at early time points and could be early indicators of a renal adaptive response to gentamicin-induced renal injury. Furthermore, the drug efficacy of gentamicin was evaluated through the detection of changes in gut microflora-related compounds (e.g. indole-containing metabolites). Metabolomics was successful in identifying valine, hydroxyproline, HVA-SO4 and HVrA-SO4 that might serve as potential early injury biomarkers or adaptive markers of gentamicin-induced renal injury, and in assessing gentamicin efficacy through changes in compounds reported to be related to gut microflora. However, caution should be taken in direct translation of the biomarkers reported in clinical settings because a much higher dose of gentamicin than the normal therapeutic dose (~1–2 mg/kg) was used to cause kidney damaged.
机译：基于LC / MS和NMR的全局代谢组学分析被用于研究庆大霉素治疗后大鼠尿液的变化。连续1天，2天或3天给Sprague–Dawley大鼠服用0、75、150或300 mg / kg /天的硫酸庆大霉素。处死每组四只动物以收获肾脏组织并在第1、2、3、7、10、15、18、22、29、36和44天收集尿液，总共11个不同的时间点。单变量和多变量统计分析均用于确定在不同剂量水平和时间点尿液中代谢产物的显着变化。酪氨酸，缬氨酸和羟脯氨酸等氨基酸的增加和减少反映了肾脏损伤发展和/或肾脏损伤恢复的组织病理学变化。注意到糖尿症比经典的肾功能生物标志物，血尿素氮和血清肌酐变化要早得多。与多巴胺有关的化合物，高香草酸硫酸盐（HVA-SO4 ）和高纯硫酸硫酸盐（HVrA-SO4 ）在早期时间点显着增加，并且可能是肾脏对庆大霉素-适应性反应的早期指标。诱发肾损伤。此外，庆大霉素的药效是通过检测肠道菌群相关化合物（例如含吲哚的代谢产物）变化来评估的。代谢组学成功地鉴定了缬氨酸，羟脯氨酸，HVA-SO4 和HVrA-SO4 ，它们可能是庆大霉素诱发的肾损伤的潜在早期损伤生物标志物或适应性标志物，并通过改变据报道与肠道菌群有关的化合物。但是，在临床环境中报道的生物标志物的直接翻译中应谨慎，因为庆大霉素的剂量要比正常治疗剂量（约1-2 mg / kg）高得多，从而导致肾脏受损。

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  • 来源
    《Metabolomics》 |2012年第6期|p.1181-1193|共13页
  • 作者

    Jinchun Sun; Sudeepa Bhattacharyya; Laura K. Schnackenberg; Lisa Pence; Yosuke Ando; Jun Zhang; Sharon Stewart; Barry Rosenzweig; Rodney Rouse; Didier Portilla; Richard D. Beger;

  • 作者单位

    Division of Systems Biology, National Center for Toxicological Research, US FDA, 3900 NCTR Road, Jefferson, AR, 72079, USA;

    Arkansas Children’s Hospital, 1 Children’s Way, Little Rock, AR, 72202-3591, USA;

    Division of Systems Biology, National Center for Toxicological Research, US FDA, 3900 NCTR Road, Jefferson, AR, 72079, USA;

    Division of Systems Biology, National Center for Toxicological Research, US FDA, 3900 NCTR Road, Jefferson, AR, 72079, USA;

    Medicinal Safety Research Labs, Daiichi Sankyo Co., Ltd., Tokyo, Japan;

    Division of Drug Safety Research, Office of Testing and Research, Office of Pharmaceutical Science, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA;

    Division of Drug Safety Research, Office of Testing and Research, Office of Pharmaceutical Science, Center for Drug Evaluation and Research, US Food and Drug Administration, Silv;

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  • 正文语种 eng
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  • 关键词

    Nephrotoxicity; Gentamicin; Biomarker; Efficacy; Dopamine; Metabolomics;

    机译：肾毒性;庆大霉素;生物标志物;功效;多巴胺;代谢组学;

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