Nakagawa Shunsaku, Nishihara Kumiko, Miyata Hitomi, Shinke Haruka, Tomita Eri, Kajiwara Moto, Matsubara Takeshi, Iehara Noriyuki, Igarashi Yoshinobu, Yamada Hiroshi, Fukatsu Atsushi, Yanagita Motoko, Matsubara Kazuo, Masuda Satohiro
Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Sakyo-ku, Kyoto, 606-8507, Japan.
Department of Nephrology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, 606-8507, Japan.
PLoS One. 2015 Aug 28;10(8):e0136994. doi: 10.1371/journal.pone.0136994. eCollection 2015.
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.
在慢性肾脏病（CKD）中，肾单位的进行性丧失会导致肾小球硬化，以及肾小管间质纤维化和进行性肾小管损伤。在本研究中，我们旨在确定反映肾小管间质纤维化和肾小管细胞损伤组织病理学进展的分子变化。从48例经组织病理学确诊为CKD的患者中获取一组肾活检样本，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四二硫键核心结构域2和NK6同源盒2在CKD中差异表达。它们的表达水平与通过组织病理学检查确定的肾小管间质纤维化和肾小管细胞损伤程度相关。在CKD的啮齿动物单侧输尿管梗阻模型中，随着肾损伤的进展，这5个基因的表达也增加。我们使用活检样本的微阵列基因表达谱计算了一个分子评分。使用该分子评分绘制的受试者操作特征曲线下的综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。在一个由5例CKD个体组成的验证组中证实了该评分的强大敏感性。这些发现确定了具有检测肾中肾小管细胞损伤和肾小管间质纤维化潜力的新型分子标志物。
