Short and long term gene expression variation and networking in human proximal tubule cells when exposed to cadmium.
Short and long term gene expression variation and networking in human proximal tubule cells when exposed to cadmium.
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DOI：
10.1186/1755-8794-6-s1-s2
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发表时间：
2013
影响因子：
2.7
通讯作者：
Zhang KK
中科院分区：
文献类型：
--
作者：
Garrett SH;Clarke K;Sens DA;Deng Y;Somji S;Zhang KK
镉 (Cd2+) 是一种已知的肾毒素，在急性接触时会导致肾小管坏死，在长期长期接触时可能会导致肾衰竭。为了研究镉引起的整体基因表达的变化，利用从肾切除术获得的皮质组织衍生的人肾上皮细胞培养物开发了体外暴露系统。这些培养物表现出近端小管细胞的许多特性。使用这些细胞进行了一项研究，以确定短期（1天、9、27和45μM）和长期镉暴露（13天、4.5、9和27μM）后镉诱导的整体基因表达变化。这些研究揭示了每个时间点表达的基因类型的根本差异。使用回归进一步分析获得的数据，以确定镉毒性反应基因。回归分析显示，1天内Cd2+诱导了403个基因，抑制了522个基因，13天后分别诱导和抑制了366个基因和517个基因。我们开发了一种基因集富集分析方法来识别与传统方法相比独特的镉诱导途径。不同 Cd2+ 浓度和多个时间点对全局基因表达的扰动使我们能够使用基于相互信息的网络模型来研究转录动力学和基因相互作用。最突出的网络模块包括 INHBA、KIF20A、DNAJA4、AKAP12、ZFAND2A、AKR1B10、SCL7A11 和 AKR1C1。
Cadmium (Cd2+) is a known nephrotoxin causing tubular necrosis during acute exposure and potentially contributing to renal failure in chronic long-term exposure. To investigate changes in global gene expression elicited by cadmium, an in-vitro exposure system was developed from cultures of human renal epithelial cells derived from cortical tissue obtained from nephrectomies. These cultures exhibit many of the qualities of proximal tubule cells. Using these cells, a study was performed to determine the cadmium-induced global gene expression changes after short-term (1 day, 9, 27, and 45 μM) and long-term cadmium exposure (13 days, 4.5, 9, and 27 μM). These studies revealed fundamental differences in the types of genes expressed during each of these time points. The obtained data was further analyzed using regression to identify cadmium toxicity responsive genes. Regression analysis showed 403 genes were induced and 522 genes were repressed by Cd2+ within 1 day, and 366 and 517 genes were induced and repressed, respectively, after 13 days. We developed a gene set enrichment analysis method to identify the cadmium induced pathways that are unique in comparison to traditional approaches. The perturbation of global gene expression by various Cd2+ concentrations and multiple time points enabled us to study the transcriptional dynamics and gene interaction using a mutual information-based network model. The most prominent network module consisted of INHBA, KIF20A, DNAJA4, AKAP12, ZFAND2A, AKR1B10, SCL7A11, and AKR1C1.