A toxicogenomic approach to assess kidney injury induced by mercuric chloride in rats

• Published in: Toxicology (Amsterdam) 2020-09, Vol.442, p.152530, Article 152530
• Main Authors: Schyman, Patric, Printz, Richard L., AbdulHameed, Mohamed Diwan M., Estes, Shanea K., Shiota, Chiyo, Shiota, Masakazu, Wallqvist, Anders
• Format: Article
• Language: English
• Subjects: Animals; Aspartate Aminotransferases - blood; Base Sequence; Biomarkers - urine; Body Weight - drug effects; Cell Adhesion Molecules - metabolism; Cell Adhesion Molecules - urine; Gene Expression - drug effects; Kidney Diseases - chemically induced; Kidney Diseases - pathology; Male; Mercuric chloride; Mercuric Chloride - toxicity; Necrosis; Nephrotoxicity; Predictive toxicology; Protein Folding - drug effects; Rats; Rats, Sprague-Dawley; RNA-seq; Toxicogenetics - methods; Toxicogenomics
• ISSN: 0300-483X; 1879-3185
• DOI: 10.1016/j.tox.2020.152530

Kidney injury caused by disease, trauma, environmental exposures, or drugs may result in decreased renal function, chronic kidney disease, or acute kidney failure. Diagnosis of kidney injury using serum creatinine levels, a common clinical test, only identifies renal dysfunction after the kidneys have undergone severe damage. Other indicators sensitive to kidney injury, such as the level of urine kidney injury molecule-1 (KIM-1), lack the ability to differentiate between injury phenotypes. To address early detection as well as detailed categorization of kidney-injury phenotypes in preclinical animal or cellular studies, we previously identified eight sets (modules) of co-expressed genes uniquely associated with kidney histopathology. Here, we used mercuric chloride (HgCl2)―a model nephrotoxicant―to chemically induce kidney injuries as monitored by KIM-1 levels in Sprague Dawley rats at two doses (0.25 or 0.50 mg/kg) and two exposure lengths (10 or 34 h). We collected whole transcriptome RNA-seq data derived from five animals at each dose and time point to perform a toxicogenomics analysis. Consistent with documented injury phenotypes for HgCl2 toxicity, our kidney-injury-module approach identified the onset of necrosis and dilation as early as 10 h after a dose of 0.50 mg/kg that produced only mild injury as judged by urinary KIM-1 excretion. The results of these animal studies highlight the potential of the kidney-injury-module approach to provide a sensitive and histopathology-specific readout of renal toxicity.