Identification of noninvasive biomarkers for nephrotoxicity using HK-2 human kidney epithelial cells

Toxicol Sci. 2014 Aug 1;140(2):247-58. doi: 10.1093/toxsci/kfu096. Epub 2014 Jun 30.

Abstract

The kidney is an important site of xenobiotic-induced toxicity. Because the traditional markers of renal injury indicate only severe renal damage, new biomarkers are needed for a more sensitive and reliable evaluation of renal toxicity. This study was designed to identify in vitro noninvasive biomarkers for efficient assessment of nephrotoxicity by using cisplatin as a model of nephrotoxic compounds. To this end, a comparative proteomic analysis of conditioned media from HK-2 human kidney epithelial cells treated with cisplatin was performed. Here, we identified pyruvate kinase M1/M2 isoform M2 (PKM2) and eukaryotic translation elongation factor 1 gamma (EF-1γ) as potential biomarker candidates for evaluation of nephrotoxicity. PKM2 and EF-1γ were increased by cisplatin in a kidney cell-specific manner, most likely due to cisplatin-induced apoptosis. The increase of PKM2 and EF-1γ levels in conditioned media was also observed in the presence of other nephrotoxic agents with different cytotoxic mechanisms such as CdCl2, HgCl2, and cyclosporine A. Rats treated with cisplatin, CdCl2, or HgCl2 presented increased levels of PKM2 and EF-1γ in the urine and kidney tissue. Taken together, this study identified two noninvasive biomarker candidates, PKM2 and EF-1γ, by comparative proteomic analysis. These new biomarkers may offer an alternative to traditional renal markers for efficient evaluation of nephrotoxicity.

Keywords: EF-1γ; HK-2; PKM2; biomarkers; conditioned media; nephrotoxicity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Biomarkers / metabolism*
  • Carrier Proteins / metabolism
  • Cell Line
  • Cisplatin / toxicity*
  • DNA Primers
  • Enzyme-Linked Immunosorbent Assay
  • Epithelial Cells / drug effects
  • Humans
  • Kidney / cytology
  • Kidney / drug effects*
  • Membrane Proteins / metabolism
  • Peptide Elongation Factor 1 / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
  • Thyroid Hormones / metabolism

Substances

  • Biomarkers
  • Carrier Proteins
  • DNA Primers
  • Membrane Proteins
  • Peptide Elongation Factor 1
  • Thyroid Hormones
  • thyroid hormone-binding proteins
  • Cisplatin