Expression data from kidneys of rats with and without cisplatin treatment

We investigated an acute kidney injury (AKI) model in rats induced by cisplatin (Cp) administration. The cisplatin is widely used since its biochemical and histopathological characteristics are representative of drug-induced AKI in humans. Male Wistar rats were dosed once ip with 0, 1 and 3 mg/kg cisplatin. Tubular necorsis was observed histopathologically in all treated rats and war recovery on day 26. Gene expression profiling of the kidney cortex with microarrays 3, 5, 8, and 26 days after single administration of 3mg/kg Cp revealed a major profile pattern characterized by maximally increased and decreased mRNA levels on day 8, with clear changes already found 3 days after treatment for about half of the mRNAs. The mRNA expression pattern after administration of 1mg/kg Cp was overall similar, yet with a dose-dependent smaller fold-change. In summary we found 274 mRNAs showing significantly altered levels in the kidney of which 162 were increased and 112 decreased, respectively. Functional interpretation of the proteins encoded by these mRNAs revealed induction of a DNA damage response likely caused by the known molecular activity of Cp as DNA alkylating agent. Increased mRNAs associated with apoptosis (encoded by the corresponding genes like B-cell lymphoma 3-encoded protein, Bcl3; mouse double minute 2 homolog, Mdm2; p21/WAF1 also known as cyclin-dependent kinase inhibitor 1), cell cycle regulation (encoded by the corresponding genes like Cyclin-G1, Ccng1; B-cell translocation gene 2, Btg2) and stress response may have partly been induced by the DNA damage, but also by the kidney damage associated with Cp administration. Increased levels of mRNAs indicating regeneration (encoded by the corresponding genes like SPARC- related modular calcium-binding protein 2, Smoc2; Tenascin C, Tnc) and decreased levels of mRNAs coding for proteins related to kidney function, indicating dedifferentiation, are likely related to the observed kidney injury.本研究针对顺铂（cisplatin, Cp）诱导的大鼠急性肾损伤（AKI）模型展开探究。顺铂因其生化与组织病理学特征可代表人类药物性急性肾损伤，故而临床应用广泛。本研究将雄性Wistar大鼠单次腹腔注射（intraperitoneal, ip）给予0、1、3 mg/kg的顺铂，所有给药大鼠均经组织病理学检测观察到肾小管坏死，并于给药后第26天恢复。对单次给予3mg/kg顺铂后的第3、5、8及26天的大鼠肾皮质进行基因表达芯片检测后发现，整体基因表达谱以第8天的信使RNA（mRNA）水平达到最大升降幅度为主要特征，且约半数mRNA在给药后3天即可出现显著表达变化。给予1mg/kg顺铂后的mRNA表达模式整体相似，但呈现出剂量依赖性的更小表达倍数变化。综上，本研究共筛选得到274个在肾脏中出现显著表达水平变化的mRNA，其中162个表达上调，112个表达下调。对这些mRNA所编码的蛋白质进行功能注释分析后发现，DNA损伤应答通路被激活，这可能与顺铂作为DNA烷化剂的已知分子活性相关。与细胞凋亡相关的上调mRNA（其编码基因包括B细胞淋巴瘤3编码蛋白（B-cell lymphoma 3-encoded protein, Bcl3）、小鼠双微体2同源物（mouse double minute 2 homolog, Mdm2）以及p21/WAF1（又称细胞周期蛋白依赖性激酶抑制剂1））、参与细胞周期调控的上调mRNA（其编码基因包括细胞周期蛋白G1（Cyclin-G1, Ccng1）、B细胞易位基因2（B-cell translocation gene 2, Btg2））以及应激反应相关的上调mRNA，其表达上调可能部分源于DNA损伤，同时也与顺铂给药引发的肾损伤相关。提示肾脏再生的上调mRNA（其编码基因包括SPARC相关模块化钙结合蛋白2（SPARC-related modular calcium-binding protein 2, Smoc2）、腱生蛋白C（Tenascin C, Tnc）），以及与肾功能相关的下调mRNA（提示细胞去分化），其表达变化均可能与本研究观察到的肾损伤相关。