title: Molecular Markers of Tubulointerstitial Fibrosis and Tubular Cell Damage in Patients with Chronic Kidney Disease.
abstract: 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.
authors: Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Sakyo-ku, Kyoto, 606-8507, Japan.
authors: Shunsaku
authors: S
authors: Nakagawa
authors: Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Sakyo-ku, Kyoto, 606-8507, Japan.
authors: Kumiko
authors: K
authors: Nishihara
authors: Department of Nephrology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, 606-8507, Japan.
authors: Hitomi
authors: H
authors: Miyata
authors: Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Sakyo-ku, Kyoto, 606-8507, Japan.
authors: Haruka
authors: H
authors: Shinke
authors: Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Sakyo-ku, Kyoto, 606-8507, Japan.
authors: Eri
authors: E
authors: Tomita
authors: Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Sakyo-ku, Kyoto, 606-8507, Japan.
authors: Moto
authors: M
authors: Kajiwara
authors: Department of Nephrology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, 606-8507, Japan.
authors: Takeshi
authors: T
authors: Matsubara
authors: Department of Nephrology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, 606-8507, Japan.
authors: Noriyuki
authors: N
authors: Iehara
authors: Toxicogenomics Informatics Project, National Institutes of Biomedical, Innovation, Health and Nutrition, 7-6-8, Saito-Asagi, Ibaraki, Osaka, 567-0085, Japan.
authors: Yoshinobu
authors: Y
authors: Igarashi
authors: Toxicogenomics Informatics Project, National Institutes of Biomedical, Innovation, Health and Nutrition, 7-6-8, Saito-Asagi, Ibaraki, Osaka, 567-0085, Japan.
authors: Hiroshi
authors: H
authors: Yamada
authors: Department of Nephrology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, 606-8507, Japan.
authors: Atsushi
authors: A
authors: Fukatsu
authors: Department of Nephrology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, 606-8507, Japan.
authors: Motoko
authors: M
authors: Yanagita
authors: Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Sakyo-ku, Kyoto, 606-8507, Japan.
authors: Kazuo
authors: K
authors: Matsubara
authors: Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Sakyo-ku, Kyoto, 606-8507, Japan.
authors: Satohiro
authors: S
authors: Masuda
mesh_terms: D000209:Acute-Phase Proteins / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000378:metabolism*; D018450:Disease Progression; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D000072596:Hepatitis A Virus Cellular Receptor 1; D006801:Humans; D007684:Kidney Tubules / Q000293:injuries / Q000378:metabolism* / Q000473:pathology*; D000071068:Lipocalin-2; D054834:Lipocalins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D011991:Receptors, Virus / Q000235:genetics / Q000378:metabolism; D051436:Renal Insufficiency, Chronic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D055758:SOX9 Transcription Factor / Q000235:genetics / Q000378:metabolism
chemical_list: D000209:Acute-Phase Proteins; D015415:Biomarkers; C491143:HAVCR1 protein, human; D000072596:Hepatitis A Virus Cellular Receptor 1; C489506:LCN2 protein, human; D000071068:Lipocalin-2; D054834:Lipocalins; D008562:Membrane Glycoproteins; D011518:Proto-Oncogene Proteins; D011991:Receptors, Virus; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human