Molecular Markers of Tubulointerstitial Fibrosis and Tubular Cell Damage in Patients with Chronic Kidney Disease.
Molecular Markers of Tubulointerstitial Fibrosis and Tubular Cell Damage in Patients with Chronic Kidney Disease.
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DOI：
10.1371/journal.pone.0136994
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Masuda S
中科院分区：
文献类型：
--
作者：
Nakagawa S;Nishihara K;Miyata H;Shinke H;Tomita E;Kajiwara M;Matsubara T;Iehara N;Igarashi Y;Yamada H;Fukatsu A;Yanagita M;Matsubara K;Masuda S
在慢性肾病（CKD）中，进行性肾单位丢失导致肾小球硬化，以及肾小管间质纤维化和进行性肾小管损伤。在这项研究中，我们的目的是确定分子变化，反映肾小管间质纤维化和肾小管细胞损伤的组织病理学进展。从48例组织病理学证实的CKD患者中获得一组肾活检标本，并通过微阵列分析确定基因表达谱。结果表明，甲型肝炎病毒细胞受体1（也称为肾损伤分子-1，KIM-1），脂质运载蛋白2（也称为中性粒细胞明胶酶相关脂质运载蛋白，NGAL），SRY盒9，WAP四硫核心结构域2和NK 6同源框2在CKD中差异表达。它们的表达水平与肾小管间质纤维化和肾小管细胞损伤的程度相关，由组织病理学检查确定。这5个基因的表达也增加了肾脏损害进展的啮齿类动物单侧输尿管梗阻模型的CKD。我们使用活检标本的微阵列基因表达谱计算分子评分。使用该分子评分绘制的受试者工作特征曲线下的复合面积显示出诊断肾小管间质纤维化和肾小管细胞损伤的高准确性。在5名CKD患者的验证集中证实了该评分的稳健灵敏度。这些发现确定了新的分子标记物，有可能有助于检测肾小管细胞损伤和肾小管间质纤维化。
In chronic kidney disease (CKD), progressive nephron loss causes glomerular sclerosis, as well as tubulointerstitial fibrosis and progressive tubular injury. In this study, we aimed to identify molecular changes that reflected the histopathological progression of renal tubulointerstitial fibrosis and tubular cell damage. A discovery set of renal biopsies were obtained from 48 patients with histopathologically confirmed CKD, and gene expression profiles were determined by microarray analysis. The results indicated that hepatitis A virus cellular receptor 1 (also known as Kidney Injury Molecule-1, KIM-1), lipocalin 2 (also known as neutrophil gelatinase-associated lipocalin, NGAL), SRY-box 9, WAP four-disulfide core domain 2, and NK6 homeobox 2 were differentially expressed in CKD. Their expression levels correlated with the extent of tubulointerstitial fibrosis and tubular cell injury, determined by histopathological examination. The expression of these 5 genes was also increased as kidney damage progressed in a rodent unilateral ureteral obstruction model of CKD. We calculated a molecular score using the microarray gene expression profiles of the biopsy specimens. The composite area under the receiver operating characteristics curve plotted using this molecular score showed a high accuracy for diagnosing tubulointerstitial fibrosis and tubular cell damage. The robust sensitivity of this score was confirmed in a validation set of 5 individuals with CKD. These findings identified novel molecular markers with the potential to contribute to the detection of tubular cell damage and tubulointerstitial fibrosis in the kidney.