ArticleJCI insight2017
Human liver-kidney model elucidates the mechanisms of aristolochic acid nephrotoxicity.
Article in JCI insight, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 89 papers, 1 of them a synthesis that pooled it.
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Who cites it
89 citing papers in PubMed, 1 synthesis or guideline pooled it, 178 citations in OpenAlex.
- Advances in Engineering Human Tissue Models.Frontiers in bioengineering and biotechnology · 2020Pooled it
- Glucagon receptor agonist aggravates a murine model of Balkan nephropathy.American journal of physiology. Renal physiology · 2026Article
- Synergistic innovation in organ-on-a-chip and organoid technologies: reshaping the future of disease modeling, drug development, and precision medicine.Protein & cell · 2026Review
- Organ-on-a-chip toxicology.Innovation (Cambridge (Mass.)) · 2026Review
- Aristolochic Acid and Hepatocellular Carcinoma: A Critical Review of Genotoxic and Inflammatory Mechanisms.International journal of molecular sciences · 2026Review
- JAK3 identified as a key toxicological target of aristolochic acid in clear cell renal cell carcinoma.Molecular diversity · 2026Article
- New Dimensions in Diabetic Kidney Disease Research: Advanced Organoids and Organs-on-a-Chip.BME frontiers · 2026Review
- Enhancing therapeutic strategies and drug development for patients with kidney disease.Expert opinion on drug safety · 2026Review
- Microphysiological Systems for Comorbidity Studies: Chronic Kidney Disease and Osteoarthritis.Advanced healthcare materials · 2025Review
- Medicinal plants of Sabah (North Borneo): lest we forget.Pharmaceutical biology · 2025Review
- Microphysiological systems as an emerging in vitro approach for the evaluation of drug absorption, distribution, metabolism, and excretion and toxicity.Drug metabolism and disposition: the biological fate of chemicals · 2025Review
- Inhibition of MCL-1 to eliminate senescent cells and mitigate renal fibrosis in aristolochic acid nephropathy.Cell death & disease · 2025Article
- The role of ferroptosis in acute kidney injury: mechanisms and potential therapeutic targets.Molecular and cellular biochemistry · 2025Review
- Stir-fried Semen Armeniacae Amarum Suppresses Aristolochic Acid I-Induced Nephrotoxicity and DNA Adducts.Chinese journal of integrative medicine · 2025Article
- Genome-Based Advances in Modeling Renal Ciliopathies and Enhancing Patient Care.Kidney & blood pressure research · 2025Review
- Vascularized tumor on a microfluidic chip to study mechanisms promoting tumor neovascularization and vascular targeted therapies.Theranostics · 2025Article
- Methodology and Practice for Studying Crosstalk Between 3D Human Tissue Models in Pneumatically Actuated Multi-Organ-on-Chip Systems.Methods in molecular biology (Clifton, N.J.) · 2025Article
- Review
- Unveiling correlations between aristolochic acids and liver cancer: spatiotemporal heterogeneity phenomenon.Chinese medicine · 2024Review
- C/EBPδ Mediates Immunity to Renal Autoinflammatory Disorders in a Stage-specific Manner.Journal of immunology (Baltimore, Md. : 1950) · 2024Article
29 more citing papers are in PubMed but not listed here.
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16 authors at 2 institutions in 1 country.
Funding
Abstract
Environmental exposures pose a significant threat to human health. However, it is often difficult to study toxicological mechanisms in human subjects due to ethical concerns. Plant-derived aristolochic acids are among the most potent nephrotoxins and carcinogens discovered to date, yet the mechanism of bioactivation in humans remains poorly understood. Microphysiological systems (organs-on-chips) provide an approach to examining the complex, species-specific toxicological effects of pharmaceutical and environmental chemicals using human cells. We microfluidically linked a kidney-on-a-chip with a liver-on-a-chip to determine the mechanisms of bioactivation and transport of aristolochic acid I (AA-I), an established nephrotoxin and human carcinogen. We demonstrate that human hepatocyte-specific metabolism of AA-I substantially increases its cytotoxicity toward human kidney proximal tubular epithelial cells, including formation of aristolactam adducts and release of kidney injury biomarkers. Hepatic biotransformation of AA-I to a nephrotoxic metabolite involves nitroreduction, followed by sulfate conjugation. Here, we identify, in a human tissue-based system, that the sulfate conjugate of the hepatic NQO1-generated aristolactam product of AA-I (AL-I-NOSO3) is the nephrotoxic form of AA-I. This conjugate can be transported out of liver via MRP membrane transporters and then actively transported into kidney tissue via one or more organic anionic membrane transporters. This integrated microphysiological system provides an ex vivo approach for investigating organ-organ interactions, whereby the metabolism of a drug or other xenobiotic by one tissue may influence its toxicity toward another, and represents an experimental approach for studying chemical toxicity related to environmental and other toxic exposures.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.