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Genome-Scale Model-Based Identification of Metabolite Indicators for Early Detection of Kidney Toxicity
Venkat R Pannala1,2, Kalyan C Vinnakota1,2, Shanea K Estes3
1Department of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Development Command, Fort Detrick, Maryland 21702.
Abstract:
Identifying early indicators of toxicant-induced organ damage is critical to provide effective treatment. To discover such indicators and the underlying mechanisms of toxicity, we used gentamicin as an exemplar kidney toxicant and performed systematic perturbation studies in Sprague Dawley rats. We obtained high-throughput data 7 and 13 h after administration of a single dose of gentamicin (0.5 g/kg) and identified global changes in genes in the liver and kidneys, metabolites in the plasma and urine, and absolute fluxes in central carbon metabolism. We used these measured changes in genes in the liver and kidney as constraints to a rat multitissue genome-scale metabolic network model to investigate the mechanism of gentamicin-induced kidney toxicity and identify metabolites associated with changes in tissue gene expression. Our experimental analysis revealed that gentamicin-induced metabolic perturbations could be detected as early as 7 h postexposure. Our integrated systems-level analyses suggest that changes in kidney gene expression drive most of the significant metabolite alterations in the urine. The analyses thus allowed us to identify several significantly enriched injury-specific pathways in the kidney underlying gentamicin-induced toxicity, as well as metabolites in these pathways that could serve as potential early indicators of kidney damage.
Insights
Early detection of kidney damage from toxicants like gentamicin is possible. This study identified specific metabolites in urine as early indicators of kidney injury within 7 hours.
Area of Science:
- Toxicology
- Metabolomics
- Systems Biology
Background:
- Early detection of toxicant-induced organ damage is crucial for timely treatment.
- Gentamicin is a common nephrotoxicant, making it a relevant model for studying kidney injury.
- Understanding the mechanisms of toxicity can lead to better diagnostic and therapeutic strategies.
Purpose of the Study:
- To identify early indicators and underlying mechanisms of gentamicin-induced kidney toxicity.
- To investigate the relationship between gene expression changes and metabolic alterations in the kidney and plasma.
- To discover potential urinary biomarkers for early kidney damage detection.
Main Methods:
- Systematic perturbation studies in Sprague Dawley rats exposed to gentamicin.
- High-throughput data collection including gene expression, plasma/urine metabolites, and metabolic fluxes.
- Integration of experimental data with a rat genome-scale metabolic network model.
Main Results:
- Metabolic perturbations indicative of kidney toxicity were detected as early as 7 hours post-gentamicin administration.
- Changes in kidney gene expression were identified as the primary drivers of significant urinary metabolite alterations.
- Specific injury-related pathways and associated metabolites in the kidney were identified.
Conclusions:
- Urinary metabolites can serve as early indicators of gentamicin-induced kidney damage.
- Kidney gene expression changes play a critical role in the metabolic consequences of nephrotoxicity.
- Integrated systems-level analysis provides a powerful approach to uncover mechanisms of organ toxicity.
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