Journal Article

Molecular Markers of Tubulointerstitial Fibrosis and Tubular Cell Damage in Patients with Chronic Kidney Disease

Miyata, Hitomi, Shinke, Haruka, Igarashi, Yoshinobu, Yanagita, Motoko, Yamada, Hiroshi, Matsubara, Kazuo, Nakagawa, Shunsaku, Fukatsu, Atsushi, Tomita, Eri, Nishihara, Kumiko, Kajiwara, Moto, Masuda, Satohiro, Iehara, Noriyuki, Matsubara, Takeshi

2015

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Acute-Phase Proteins - genetics / Acute-Phase Proteins - metabolism / Adult / Aged / Biomarkers / Biomarkers - metabolism / Biopsy / Cell injury / Damage detection / Development and progression / Disease Progression / DNA microarrays / Female / Fibrosis / Gelatinase / Gene expression / Gene Expression Profiling - methods / Gene Expression Regulation / Genetic aspects / Genotypes / Health aspects / Hepatitis / Hepatitis A / Hepatitis A Virus Cellular Receptor 1 / Homeobox / Hospitals / Humans / Identification and classification / Informatics / Injuries / Kidney diseases / Kidney Tubules - injuries / Kidney Tubules - metabolism / Kidney Tubules - pathology / Kidneys / Lipocalin / Lipocalin-2 / Lipocalins - genetics / Lipocalins - metabolism / Male / Markers / Medicine / Membrane Glycoproteins - genetics / Membrane Glycoproteins - metabolism / Middle Aged / Molecular chains / Nephrology / Oligonucleotide Array Sequence Analysis - methods / Patients / Pharmacology / Proteins / Proto-Oncogene Proteins - genetics / Proto-Oncogene Proteins - metabolism / Receptors, Virus - genetics / Receptors, Virus - metabolism / Renal Insufficiency, Chronic - genetics / Renal Insufficiency, Chronic - metabolism / Renal Insufficiency, Chronic - pathology / Rodents / Sclerosis / SOX9 Transcription Factor - genetics / SOX9 Transcription Factor - metabolism / Studies / Transplants & implants / Urine / Viruses