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A toxicogenomic approach to assess kidney injury induced by mercuric chloride in rats
Patric Schyman1, Richard L Printz2, Mohamed Diwan M AbdulHameed1
1DoD Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Development Command, Fort Detrick, MD, USA; The Henry M. Jackson Foundation for the Advancement of Military Medicine Inc., Bethesda, MD, USA.
Abstract:
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.
Insights
This study introduces a novel gene module approach for early and specific detection of kidney injury in animal models. This method identifies toxic effects before significant functional decline, improving toxicogenomics analysis.
Area of Science:
- Toxicology
- Renal Physiology
- Molecular Biology
Background:
- Kidney injury diagnosis via serum creatinine is often delayed.
- Existing biomarkers like KIM-1 lack specificity for injury types.
- Early and specific detection of kidney injury is crucial for preclinical studies.
Purpose of the Study:
- To evaluate a novel kidney injury module approach for early and specific detection of renal toxicity.
- To assess the utility of gene co-expression modules in categorizing kidney injury phenotypes.
- To validate the approach using a mercuric chloride (HgCl2) induced kidney injury model in rats.
Main Methods:
- Induction of kidney injury in Sprague Dawley rats using two doses of HgCl2 and two exposure durations.
- Monitoring of kidney injury using urinary KIM-1 levels.
- Whole transcriptome RNA-sequencing (RNA-seq) data collection from rat kidneys.
- Application of a previously identified kidney-injury-module approach for toxicogenomics analysis.
Main Results:
- The kidney-injury-module approach detected necrosis and dilation as early as 10 hours post-HgCl2 exposure.
- This early detection occurred even with mild injury indicated by urinary KIM-1 levels.
- The gene module approach provided histopathology-specific insights into renal toxicity.
Conclusions:
- The kidney-injury-module approach offers a sensitive method for early detection of kidney injury.
- This approach can differentiate specific kidney histopathology phenotypes.
- The findings support the use of gene modules for detailed toxicogenomics analysis in renal research.
