Gene expression approach to evaluate kidney injury molecule-1 (KIM-1) as a predictive marker for renal toxicity

Sensitive and specific biomarkers are needed to detect early kidney injury. Gene expression analysis applied to toxicology is actively being employed in drug discovery, in the attempt to identify potential biomarkers of toxicity for various organs. The objective of the present work was to evaluate if Kidney Injury Molecule-1 (KIM-1) can be considered a sensitive molecular marker to identify renal injury in the rodent. KIM-1 mRNA levels were monitored by qRT-PCR in renal tissue after treatment with segment-specific nephrotoxicants in dose-range and time-course studies. For the biological validation of the marker, transcript changes were correlated with histopathological findings and clinical markers (plasmatic creatinine and urea, renal glutamine synthetase (GS), urinary N-acetyl-glucosamine (NAG) and -glutamyl-transferase (GGT)) of renal damage. Male Wistar rats (8-weeks old) received (single administration) 25, 50, and 100 mg/kg hexachloro-1:3-butadiene (HCBD), or 8, 12.5, and 25 mg/kg potassium dichromate (Cr) in the dose-range and 100 mg/kg b.w. HCBD, or 25 mg/kg b.w. Cr in the time-course study. Samples were collected at 48h (dose-range) or at 6, 12, 24, 48, 72, and 96h (time-course) after treatment. A kidney portion was processed through molecular biology techniques for KIM-1 quantification. Segment-specific toxicity induced by HCBD (pars recta) or Cr (pars convoluta) was accompanied by dose- and time-related modifications in KIM-1 mRNA fold changes. KIM-1 transcript showed high sensitivity and prediction being up-regulated also when minimal findings or no abnormalities were observed at histopathology. Functional markers of renal toxicity were modified only when clear evidence of damage were detected by histopathology and gene expression. In conclusion, KIM-1 gene response in renal tissue appears an early and sensitive tool to assess kidney tubular injury and repair induced by xenobiotics. This work confirmed that gene expression approach can be considered a powerful and easy-to-use technique for identification and evaluation of new toxicity markers.