Evaluation of molecular markers of renal toxicity caused by segment-specific nephrotoxicants for the proximal tubule

Identification of novel biomarkers of kidney toxicity is one of the main applications of genomic-based technologies. The aim of the present research was to measure by qRT-PCR mRNA levels of genes expressed in the injured and/or regenerating kidney cells after treatment with segment-specific nephrotoxicants. Male Wistar rats (8 weeks old) received 25, 50, and 100 mg/kg hexachloro-1:3-butadiene (HCBD), or 8, 12.5, and 25 mg/kg of potassium dichromate (Cr). 48 hours after treatment, rats were killed and a portion of the kidney was processed to qRT-PCR. The following genes were valuated: kidney injury molecule-1 (KIM-1), clusterin (Cln), regucalcin (Rgn), and osteopontin (Spp1) according to their involvement in tissue damage, remodelling and regeneration, disruption of calcium homeostasis, oxidative stress. In addition, a kidney portion was processed for histopathological examination and blood was sampled for creatinine and urea measurement. Segment-specific toxicity induced by HCBD (pars recta) or Cr (pars convoluta) was accompanied by dose-related modifications in gene expression, in terms of number of genes involved and in their fold changes. In detail, at high doses with Cr the damage involved also distal portion of the tubule, possibly related with transcript higher response. From selected genes, KIM-1 showed better sensitivity being still increased at low doses, despite no abnormalities were detected with HCBD and minimal findings with Cr. Urea and creatinine were increased at high doses only, thus resulting not very sensitive. In conclusion, genomic responses well correlate with traditional morphological and clinical endpoints and possibly could represent more sensitive tool to monitor nephrotoxicity.