Identification of neutrophil gelatinase-associated lipocalin as a novel early urinary biomarker for ischemic renal injury
Identification of neutrophil gelatinase-associated lipocalin as a novel early urinary biomarker for ischemic renal injury
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DOI：
10.1097/01.asn.0000088027.54400.c6
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发表时间：
2003-10-01
影响因子：
13.6
通讯作者：
Devarajan, P
中科院分区：
文献类型：
--
作者：
Mishra, J;Ma, Q;Devarajan, P
继发于缺血性损伤的急性肾功能衰竭(ARF)仍然是一个常见且具有潜在破坏性的问题。采用全转录组询问策略来鉴定肾缺血后早期诱导的肾脏基因，其蛋白产物可能作为新的生物标志物用于鉴定7个上调10倍的基因，其中之一(Cyr6I)最近被报道在肾缺血后诱导。出乎意料的是，其他六个转录本的诱导对ARF领域来说是新的。在这项研究中，其中一个以前未被识别的基因被进一步鉴定，即中性粒细胞明胶酶相关的Lipocalin(NGAL)，因为它是一种小的分泌型多肽，对蛋白酶具有抵抗力，因此很容易在尿液中检测到。证实了NGAL在小鼠缺血早期肾脏中的表达水平显著上调。NGAL蛋白主要在增殖细胞核抗原阳性的近端小管细胞中表达，呈点状分布，与晚期内小体的标记共存。在小鼠和大鼠肾缺血模型中，NGAL的出现与肾缺血的剂量和时间有关，并先于其他尿液标志物如N-乙酰-β-D-氨基葡萄糖苷酶和β2-微球蛋白的出现。体外培养的人近端肾小管上皮细胞受到缺血损伤后，NGAL基因在细胞内迅速被诱导，并且在轻度的ATP耗竭后1h内，培养上清液中可检测到NGAL蛋白。在顺铂肾毒性小鼠的尿液中也很容易检测到NGAL，同样早于N-乙酰-β-D-氨基葡萄糖苷酶和β2-微球蛋白的出现。提示NGAL可作为早期、灵敏、无创的尿液生物标志物，用于诊断缺血性肾损伤和肾毒性肾损伤。
Acute renal failure (ARF) secondary to ischemic injury remains a common and potentially devastating problem. A transcriptome-wide interrogation strategy was used to identify renal genes that are induced very early after renal ischemia, whose protein products might serve as novel biomarkers for ARE Seven genes that are upregulated >10-fold were identified, one of which (Cyr6I) has recently been reported to be induced after renal ischemia. Unexpectedly, the induction of the other six transcripts was novel to the ARF field. In this study, one of these previously unrecognized genes was further characterized, namely neutrophil gelatinase-associated lipocalin (NGAL), because it is a small secreted polypeptide that is protease resistant and consequently might be readily detected in the urine. The marked upregulation of NGAL mRNA and protein levels in the early postischemic mouse kidney was confirmed. NGAL protein expression was detected predominantly in proliferating cell nuclear antigen-positive proximal tubule cells, in a punctate cytoplasmic distribution that colocalized with markers of late endosomes. NGAL was easily detected in the urine in the very first urine output after ischemia in both mouse and rat models of ARE The appearance of NGAL in the urine was related to the dose and duration of renal ischemia and preceded the appearance of other urinary markers such as N-acetyl-beta-D-glucosaminidase and beta2-microglobulin. The origin of NGAL from tubule cells was confirmed in cultured human proximal tubule cells subjected to in vitro ischemic injury, where NGAL mRNA was rapidly induced in the cells and NGAL protein was readily detectable in the culture medium within I h of mild ATP depletion. NGAL was also easily detectable in the urine of mice with cisplatin-induced nephrotoxicity, again preceding the appearance of N-acetyl-beta-D-glucosaminidase and beta2-microglobulin. The results indicate that NGAL may represent an early, sensitive, noninvasive urinary biomarker for ischemic and nephrotoxic renal injury.