MCP-1 Gene Activation Marks Acute Kidney Injury
MCP-1 Gene Activation Marks Acute Kidney Injury
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DOI：
10.1681/asn.2010060641
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发表时间：
2011-01-01
影响因子：
13.6
通讯作者：
Zager, Richard A.
中科院分区：
文献类型：
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作者：
Munshi, Raj;Johnson, Ali;Zager, Richard A.
单核细胞趋化蛋白1（MCP-1）介导急性缺血性和毒性肾损伤，但这是否可以作为急性肾损伤（阿基）的生物标志物是未知的。我们从肾内（马来酸盐）、肾前（内毒素血症）或肾后（输尿管梗阻）损伤的小鼠中获取肾脏和尿液样本。我们还通过在小鼠中进行双侧输尿管横断来研究尿毒症的独立影响，而没有伴随肾损伤。此外，我们从APACHE II匹配的伴有或不伴有进展性氮质血症的危重患者（每组n = 10）中获得尿液样本。我们分析了选定样本的MCP-1、MCP-1 mRNA和MCP-1基因尿片段的活化组蛋白标记（H3 K4 m3），并将结果与中性粒细胞明胶酶相关脂质运载蛋白（NGAL）（一种比较“阿基生物标志物”基因）的结果进行了对比。麦芽糖醇增加尿MCP-1蛋白和mRNA比相应的增加NGAL。内毒素血症和输尿管梗阻也增加了NGAL和MCP-1基因表达。在没有肾损伤的情况下，尿毒症诱导NGAL基因，但不诱导MCP-1，这表明MCP-1对阿基具有更好的特异性。临床评估支持MCP-1作为生物标志物的效用（例如，在有和没有阿基的患者中，尿MCP-1的浓度不重叠）。尿MCP-1 mRNA水平升高和MCP-1基因H3 K4 m3水平升高支持肾损伤患者MCP-1基因活化。总之，这些数据表明MCP-1具有作为阿基的生物标志物的潜力，并提供了尿组蛋白评估在肾病患者中提供机制洞察的“概念证明”。
Monocyte chemoattractant protein 1 (MCP-1) mediates acute ischemic and toxic kidney injury, but whether this can be used as a biomarker of acute kidney injury (AKI) is unknown. We obtained kidney and urine samples from mice with intrarenal (maleate), prerenal (endotoxemia), or postrenal (ureteral obstruction) injury. We also studied the independent effects of uremia without concomitant kidney injury by performing bilateral ureteral transection in mice. Additionally, we obtained urine samples from APACHE II-matched critically ill patients with or without advancing azotemia (n = 10 in each group). We assayed selected samples for MCP-1, MCP-1 mRNA, and for an activating histone mark (H3K4m3) at urinary fragments of the MCP-1 gene and contrasted the results with those obtained for neutrophil gelatinase-associated lipocalin (NGAL), a comparator "AKI biomarker" gene. Maleate increased urinary MCP-1 protein and mRNA more than the corresponding increases in NGAL. Endotoxemia and ureteral obstruction also increased NGAL and MCP-1 gene expression. Uremia, in the absence of renal injury, induced the NGAL gene, but not MCP-1, suggesting the possibility of better specificity of MCP-1 for AKI. Clinical assessments supported the utility of MCP-1 as a biomarker (e.g., nonoverlapping concentrations of urinary MCP-1 in patients with and without AKI). Elevated levels of urinary MCP-1 mRNA and levels of H3K4m3 at the MCP-1 gene supported MCP-1 gene activation in patients with renal injury. In conclusion, these data suggest that MCP-1 has potential as a biomarker of AKI and provide "proof of concept" that urinary histone assessments provide mechanistic insight among patients with kidney disease.