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Updated: Aug 6, 2026
Modeling Hypoxia/Reoxygenation Injury in Proximal Tubular Epithelial Cells
Published on: November 21, 2025
A systems-level integration of liver-kidney transcriptomics and genome-scale metabolic models reveals organ-specific
Venkat R Pannala1,2, Archana Hari1,2, Scott S Auerbach3
1Department of War Biotechnology High Performance Computing Software Applications Institute, Defense Health Agency Research & Development, Medical Research and Development Command, Fort Detrick, MD, United States.
Abstract:
The liver and kidneys are the primary organs that clear chemicals from the body, yet they often exhibit different pathological responses to the same systemic exposure. While high-throughput transcriptomics (HTT) can map broad molecular perturbations, identifying the differential mechanisms that govern organ-specific injury remains a challenge. To address this knowledge gap, we investigated the dose-dependent effects of three peroxisome proliferator-activated receptor alpha agonists-coumarin, fenofibrate, and perfluorooctanoic acid (PFOA)-on liver and kidney metabolism to understand the organ-specific mechanisms of toxicity. We used HTT data from 5-day in vivo rat exposure studies and performed a comparative analysis on the paired liver and kidney data, using gene co-expression and pathway enrichment analyses together with genome-scale models, to investigate their differential sensitivity to chemical exposure. Our results revealed that all three chemicals caused larger gene perturbations in the liver compared to the kidney, in agreement with their well-known hepatotoxicity. Fenofibrate and PFOA triggered a profound upregulation in pathways related to fatty acid metabolism but suppressed several pathways related to amino acid metabolism in both organs. All three chemicals showed a strong upregulated antioxidant response in the liver, indicating an adaptive response to chemical stress, with fenofibrate and PFOA entering uncontrolled endoplasmic reticulum stress, which was also observed for PFOA in the kidney. Our comparative analysis revealed a striking divergence in cellular repair mechanisms in response to stress across both tissues: while the liver strongly upregulated apoptotic and cell-cycle repair pathways, signaling active hepatotoxicity, the kidney consistently downregulated these same vital processes in response to all three chemicals, indicating differential mechanisms that may lead to organ toxicity.
Insights
This study reveals that liver and kidney cells respond differently to chemical exposure. While the liver shows active repair and stress responses, the kidney downregulates these vital processes, leading to organ-specific toxicity.
Area of Science:
- Toxicology
- Molecular Biology
- Systems Biology
Background:
- Liver and kidneys are key detoxification organs but show distinct pathological responses to systemic chemical exposure.
- High-throughput transcriptomics (HTT) can identify molecular changes but struggles to pinpoint organ-specific injury mechanisms.
- Understanding differential toxicity mechanisms is crucial for predicting and preventing chemical-induced organ damage.
Purpose of the Study:
- To investigate the dose-dependent effects of three peroxisome proliferator-activated receptor alpha agonists (coumarin, fenofibrate, PFOA) on liver and kidney metabolism.
- To elucidate the organ-specific mechanisms of toxicity by comparing molecular responses in paired liver and kidney tissues.
- To identify differential cellular repair pathways activated or suppressed in response to chemical stress.
Main Methods:
- Utilized HTT data from 5-day in vivo rat exposure studies.
- Performed comparative analysis of paired liver and kidney transcriptomic data.
- Employed gene co-expression, pathway enrichment analyses, and genome-scale models to assess differential sensitivity and mechanisms.
Main Results:
- All three chemicals induced greater gene perturbations in the liver than in the kidney.
- Fenofibrate and PFOA significantly altered fatty acid and amino acid metabolism pathways in both organs.
- A strong antioxidant response and endoplasmic reticulum stress were observed in the liver, with fenofibrate and PFOA also inducing ER stress in the kidney.
- The liver upregulated apoptotic and cell-cycle repair pathways, while the kidney downregulated these pathways, indicating divergent cellular repair responses.
Conclusions:
- Chemicals caused more significant molecular changes in the liver, aligning with known hepatotoxicity.
- Distinct adaptive and stress responses were observed between liver and kidney tissues.
- Differential regulation of cellular repair pathways in the liver versus the kidney highlights unique mechanisms contributing to organ-specific toxicity.
