Ghorbel Mohamed T, Patel Nishith N, Sheikh Maimuna, Angelini Gianni D, Caputo Massimo, Murphy Gavin J
Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Level 7, Bristol Royal Infirmary; Upper Maudlin Street, Bristol BS2 8HW, UK.
BMC Genomics. 2014 Oct 21;15(1):916. doi: 10.1186/1471-2164-15-916.
Acute kidney injury (AKI) is a common and serious complication of cardiac surgery using cardiopulmonary bypass (CPB). The pathogenesis is poorly understood and the study of AKI in rodent models has not led to improvements in clinical outcomes. We sought to determine the changes in renal medullary gene expression in a novel and clinically relevant porcine model of CPB-induced AKI.
Adult pigs (n = 12 per group) were randomised to undergo sham procedure, or 2.5 hours CPB. AKI was determined using biochemical (Cr51 EDTA clearance, CrCl, urinary IL-18 release) and histological measures. Transcriptomic analyses were performed on renal medulla biopsies obtained 24 hours post intervention or from sham group. Microarray results were validated with real-time polymerase chain reaction and Western Blotting.Of the transcripts examined, 66 were identified as differentially expressed in CPB versus Sham pig's kidney samples, with 19 (29%) upregulated and 47 (71%) down-regulated. Out of the upregulated and downregulated transcripts 4 and 16 respectively were expression sequence tags (EST). The regulated genes clustered into three classes; Immune response, Cell adhesion/extracellular matrix and metabolic process. Upregulated genes included Factor V, SLC16A3 and CKMT2 whereas downregulated genes included GST, CPE, MMP7 and SELL.
Post CPB AKI, as defined by clinical criteria, is characterised by molecular changes in renal medulla that are associated with both injury and survival programmes. Our observations highlight the value of large animal models in AKI research and provide insights into the failure of findings in rodent models to translate into clinical progress.
急性肾损伤（AKI）是体外循环（CPB）心脏手术常见且严重的并发症。其发病机制尚不清楚，在啮齿动物模型中对AKI的研究尚未带来临床结局的改善。我们试图确定在一种新型且与临床相关的CPB诱导的AKI猪模型中肾髓质基因表达的变化。
成年猪（每组n = 12）被随机分配接受假手术或2.5小时的CPB。使用生化指标（Cr51 EDTA清除率、CrCl、尿IL-18释放）和组织学方法确定AKI。在干预后24小时从假手术组或CPB组获取肾髓质活检组织进行转录组分析。通过实时聚合酶链反应和蛋白质免疫印迹法验证微阵列结果。在所检测的转录本中，66个被鉴定为在CPB组与假手术组猪的肾脏样本中差异表达，其中19个（29%）上调，47个（71%）下调。在上调及下调的转录本中，分别有4个和16个是表达序列标签（EST）。调控的基因聚为三类：免疫反应、细胞黏附/细胞外基质和代谢过程。上调的基因包括凝血因子V、溶质载体家族16成员3和肌酸激酶线粒体2型，而下调的基因包括谷胱甘肽S转移酶、羧肽酶E、基质金属蛋白酶7和淋巴细胞功能相关抗原1。
根据临床标准定义，CPB后AKI的特征是肾髓质的分子变化，这些变化与损伤和存活程序相关。我们的观察结果突出了大型动物模型在AKI研究中的价值，并为啮齿动物模型研究结果未能转化为临床进展提供了见解。
