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

PLoS One. 2015 Aug 28;10(8):e0136994. doi: 10.1371/journal.pone.0136994. eCollection 2015.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute-Phase Proteins / genetics
  • Acute-Phase Proteins / metabolism
  • Adult
  • Aged
  • Biomarkers / metabolism*
  • Disease Progression
  • Female
  • Gene Expression Profiling / methods
  • Gene Expression Regulation
  • Hepatitis A Virus Cellular Receptor 1
  • Humans
  • Kidney Tubules / injuries
  • Kidney Tubules / metabolism*
  • Kidney Tubules / pathology*
  • Lipocalin-2
  • Lipocalins / genetics
  • Lipocalins / metabolism
  • Male
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism
  • Middle Aged
  • Oligonucleotide Array Sequence Analysis / methods
  • 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*
  • SOX9 Transcription Factor / genetics
  • SOX9 Transcription Factor / metabolism

Substances

  • Acute-Phase Proteins
  • Biomarkers
  • HAVCR1 protein, human
  • Hepatitis A Virus Cellular Receptor 1
  • LCN2 protein, human
  • Lipocalin-2
  • Lipocalins
  • Membrane Glycoproteins
  • Proto-Oncogene Proteins
  • Receptors, Virus
  • SOX9 Transcription Factor
  • SOX9 protein, human

Grant support

This work was supported in part by a grant-in-aid for Research on Biological Markers for New Drug Development and Health and Labour Sciences Research Grants from the Ministry of Health, Labour and Welfare of Japan (08062855 to S. Masuda); by a Funding Program for Next Generation World-Leading Researchers (NEXT Program: LS073 to S. Masuda) initiated by the Council for Science and Technology Policy of the Japan Society for the Promotion of Science; and by a Grant-in-Aid for Scientific Research (KAKENHI) from the Ministry of Education, Science, Culture, Sports, and Technology of Japan (MEXT) of Japan.