Evaluation of Protein Biomarkers for Renal Toxicity Induced by Exposure to Low-dose Heavy Metals

Abstract

Kidney is one of the main targets for toxicity induced by xenobiotics including drugs and heavy metals. The biomarkers to detect xenobiotic-induced nephrotoxicity are being actively developed, but the sensitivity and efficiency of these biomarkers still need to be improved. The aim of this study is to identify novel biomarkers using proteomic approaches in xenobiotic-exposed kidney tissue. Mercuric chloride (HgCl2) was administered by oral route in the drinking water to male Sprague-Dawley rats every two days for 14 days. Proteomic analysis with kidney samples revealed that AKR7A1 and GSTP1 were significantly elevated by mercury exposure, suggesting them as potential candidates for new nephrotoxic biomarkers. Interestingly, in normal rat kidney proximal tubular cells (NRK-52E), the change of expression level of AKR7A1 and GSTP1 was well correlated to the extent of cytotoxicity induced by exposure to nephrotoxicants of heavy metals (Hg and Cd) and cisplatin. The sensitivity of these two biomarkers was found to be superior to that of traditional biomarkers for renal toxicity, such as Kim1, Lcn2, Spp1 and TIMP1. With this study, we identified AKR7A1 and GSTP1 as new candidates for drug or heavy metal-induced renal toxicity. Correlation between cytotoxicity and the extent of AKR7A1 and GSTP1 change suggests that they can be useful biomarkers to evaluate or predict renal toxicity.