Assessing Kidney Injury Induced by Mercuric Chloride in Guinea Pigs with In Vivo and In Vitro Experiments.
Assessing Kidney Injury Induced by Mercuric Chloride in Guinea Pigs with In Vivo and In Vitro Experiments.
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DOI：
10.3390/ijms24087434
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发表时间：
2023-04-18
影响因子：
5.6
通讯作者：
Wallqvist, Anders
中科院分区：
文献类型：
--
作者：
Goel, Himanshu;Printz, Richard L.;Shiota, Chiyo;Estes, Shanea K.;Pannala, Venkat;AbdulHameed, Mohamed Diwan M.;Shiota, Masakazu;Wallqvist, Anders
急性肾损伤与高水平的发病率和死亡率相关，影响大量个体，并且可以由多种因素触发，例如药物、暴露于有毒化学品或其他物质、疾病和创伤。由于肾脏是一个关键器官，了解和识别早期细胞或基因水平的变化可以为设计医疗干预措施提供基础。在我们早期的工作中，我们确定了与毒物诱导的肝和肾损伤相关的组织病理学表型的基因模块。在这里，使用在体内和体外实验，我们评估和验证这些肾损伤相关的模块，通过分析基因表达数据的雄性哈特利豚鼠暴露于氯化汞的肾脏。使用血浆肌酐水平和细胞活力测定作为体内和体外条件下肾功能不全程度的测量，我们进行了初步的范围探索研究，以确定与轻度和重度肾损伤相关的适当剂量和暴露时间。然后，我们监测肾脏基因表达的变化，在选定的剂量和时间点后毒物暴露的特点，肾损伤的机制。我们基于损伤模块的分析揭示了与扩张、坏死和纤维化相关的几种表型细胞过程的剂量依赖性激活，这些表型细胞过程在实验平台中很常见，并指示启动肾损伤的过程。此外，豚鼠和大鼠之间的激活损伤模块的比较表明模块之间的强相关性，突出了它们的跨物种翻译研究的潜力。
Acute kidney injury, which is associated with high levels of morbidity and mortality, affects a significant number of individuals, and can be triggered by multiple factors, such as medications, exposure to toxic chemicals or other substances, disease, and trauma. Because the kidney is a critical organ, understanding and identifying early cellular or gene-level changes can provide a foundation for designing medical interventions. In our earlier work, we identified gene modules anchored to histopathology phenotypes associated with toxicant-induced liver and kidney injuries. Here, using in vivo and in vitro experiments, we assessed and validated these kidney injury-associated modules by analyzing gene expression data from the kidneys of male Hartley guinea pigs exposed to mercuric chloride. Using plasma creatinine levels and cell-viability assays as measures of the extent of renal dysfunction under in vivo and in vitro conditions, we performed an initial range-finding study to identify the appropriate doses and exposure times associated with mild and severe kidney injuries. We then monitored changes in kidney gene expression at the selected doses and time points post-toxicant exposure to characterize the mechanisms of kidney injury. Our injury module-based analysis revealed a dose-dependent activation of several phenotypic cellular processes associated with dilatation, necrosis, and fibrogenesis that were common across the experimental platforms and indicative of processes that initiate kidney damage. Furthermore, a comparison of activated injury modules between guinea pigs and rats indicated a strong correlation between the modules, highlighting their potential for cross-species translational studies.
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