Human liver-kidney model elucidates the mechanisms of aristolochic acid nephrotoxicity

Chang, Sang‐Yoon; Weber, Elijah; Sidorenko, Viktoriya S.; Chapron, Alenka; Yeung, Catherine K.; Gao, Chunying; Mao, Qingcheng; Shen, Danny D.; Wang, Joanne; Rosenquist, Thomas A.; Dickman, Kathleen G.; Neumann, Thomas; Grollman, Arthur P.; Kelly, Edward J.; Himmelfarb, Jonathan; Eaton, David L.

doi:10.1172/jci.insight.95978

Cited by 150 publications

(112 citation statements)

References 40 publications

(49 reference statements)

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“…One 2017 study demonstrated that human proximal tubules on a chip showed increased KIM1 production and cell death in response to aristolochic acid I when a hepatocyte-containing chip was coupled upstream compared with when the proximal tubule chip was isolated, consistent with bioactivation of aristolochic acid I by hepatocytes 143 . This study provides proof of concept that a multiorgan in vitro model can assess the nephrotoxicity of a test compound and its metabolites.…”

Section: Preclinical Screens Of Nephrotoxicitymentioning

confidence: 99%

“…Kidneys-on-a-chip have also been used in in vitro systems to model multiorgan toxicity and pharmacodynamics, whereby the kidney chip is functionally coupled (via the manual transfer of media) or physically coupled to in vitro models of other organ systems 142,143 . One 2017 study demonstrated that human proximal tubules on a chip showed increased KIM1 production and cell death in response to aristolochic acid I when a hepatocyte-containing chip was coupled upstream compared with when the proximal tubule chip was isolated, consistent with bioactivation of aristolochic acid I by hepatocytes 143 .…”

Section: Preclinical Screens Of Nephrotoxicitymentioning

confidence: 99%

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Advances in predictive in vitro models of drug-induced nephrotoxicity

et al. 2018

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In vitro screens for nephrotoxicity are currently poorly predictive of toxicity in humans. Although the functional proteins that are expressed by nephron tubules and mediate drug susceptibility are well known, current in vitro cellular models poorly replicate both the morphology and the function of kidney tubules and therefore fail to demonstrate injury responses to drugs that would be nephrotoxic in vivo. Advances in protocols to enable the directed differentiation of pluripotent stem cells into multiple renal cell types and the development of microfluidic and 3D culture systems have opened a range of potential new platforms for evaluating drug nephrotoxicity. Many of the new in vitro culture systems have been characterized by the expression and function of transporters, enzymes, and other functional proteins that are expressed by the kidney and have been implicated in drug-induced renal injury. In vitro platforms that express these proteins and exhibit molecular biomarkers that have been used as readouts of injury demonstrate improved functional maturity compared with static 2D cultures and represent an opportunity to model injury to renal cell types that have hitherto received little attention. As nephrotoxicity screening platforms become more physiologically relevant, they will facilitate the development of safer drugs and improved clinical management of nephrotoxicants.

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Section: Preclinical Screens Of Nephrotoxicitymentioning

confidence: 99%

Section: Preclinical Screens Of Nephrotoxicitymentioning

confidence: 99%

Advances in predictive in vitro models of drug-induced nephrotoxicity

et al. 2018

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“…For evaluation of such organ-to-organ interplay, a liver-kidney combined microphysiological system has been used to demonstrate how metabolites of aristolochic acid cause kidney toxicity. 59 In that study, the nitroreduction of aristolochic acid in the liver chip followed by sulfate conjugation and active uptake transport by organic anion transporter 1 into tubular cells in the kidney chip was demonstrated. This example illustrates the unique opportunity to evaluate complex metabolismtransport interplay between organs using linked microphysiological tissue models.…”

Section: Metabolismmentioning

confidence: 95%

“…The full potential of liver chips can perhaps be realized via the use of these systems in combination with other organs, as metabolism in the liver is typically considered the culprit in forming metabolites that may then cause toxicities in other organs. For evaluation of such organ‐to‐organ interplay, a liver–kidney combined microphysiological system has been used to demonstrate how metabolites of aristolochic acid cause kidney toxicity . In that study, the nitroreduction of aristolochic acid in the liver chip followed by sulfate conjugation and active uptake transport by organic anion transporter 1 into tubular cells in the kidney chip was demonstrated.…”

Section: Use Of Microphysiological Systems To Support Pbpk Modeling Amentioning

confidence: 99%

Emerging Role of Organ‐on‐a‐Chip Technologies in Quantitative Clinical Pharmacology Evaluation

Isoherranen

Madabushi

Huang

2019

Clinical Translational Sci

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The recently enacted Prescription Drug User Fee Act ( PDUFA ) VI includes in its performance goals “enhancing regulatory science and expediting drug development.” The key elements in “enhancing regulatory decision tools to support drug development and review” include “advancing model‐informed drug development ( MIDD ).” This paper describes (i) the US Food and Drug Administration ( FDA ) Office of Clinical Pharmacology's continuing efforts in developing quantitative clinical pharmacology models (disease, drug, and clinical trial models) to advance MIDD , (ii) how emerging novel tools, such as organ‐on‐a‐chip technologies or microphysiological systems, can provide new insights into physiology and disease mechanisms, biomarker identification and evaluation, and elucidation of mechanisms of adverse drug reactions, and (iii) how the single organ or linked organ microphysiological systems can provide critical system parameters for improved physiologically‐based pharmacokinetic and pharmacodynamic evaluations. Continuous public‐private partnerships are critical to advance this field and in the application of these new technologies in drug development and regulatory review.

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“…Recently, a study by Chang and colleagues, using microphysiological systems (organs-on-chips), demonstrated that sulfotransferases (SULTs) were involved in enhancement of AA nephrotoxicity. They showed that, after nitroreduction of AAI mediated by NQO1 into aristolactam I (AL-I), the latter was converted into aristolactam-N-sulfate (AL-NOSO3H), a toxic metabolite that was transported out of the liver via multidrug resistance-associated protein (MRP) transporters, and then taken into the kidney via organic anion transporters (OATs), and formed high DNA adducts levels [37].…”

Section: Enzymatic Metabolization Of Aa Leading To the Formation Of Dmentioning

confidence: 99%

Aristolochic Acid-Induced Nephrotoxicity: Molecular Mechanisms and Potential Protective Approaches

Anger

2020

IJMS

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Aristolochic acid (AA) is a generic term that describes a group of structurally related compounds found in the Aristolochiaceae plants family. These plants have been used for decades to treat various diseases. However, the consumption of products derived from plants containing AA has been associated with the development of nephropathy and carcinoma, mainly the upper urothelial carcinoma (UUC). AA has been identified as the causative agent of these pathologies. Several studies on mechanisms of action of AA nephrotoxicity have been conducted, but the comprehensive mechanisms of AA-induced nephrotoxicity and carcinogenesis have not yet fully been elucidated, and therapeutic measures are therefore limited. This review aimed to summarize the molecular mechanisms underlying AA-induced nephrotoxicity with an emphasis on its enzymatic bioactivation, and to discuss some agents and their modes of action to reduce AA nephrotoxicity. By addressing these two aspects, including mechanisms of action of AA nephrotoxicity and protective approaches against the latter, and especially by covering the whole range of these protective agents, this review provides an overview on AA nephrotoxicity. It also reports new knowledge on mechanisms of AA-mediated nephrotoxicity recently published in the literature and provides suggestions for future studies.

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Human liver-kidney model elucidates the mechanisms of aristolochic acid nephrotoxicity

Cited by 150 publications

References 40 publications

Advances in predictive in vitro models of drug-induced nephrotoxicity

Advances in predictive in vitro models of drug-induced nephrotoxicity

Emerging Role of Organ‐on‐a‐Chip Technologies in Quantitative Clinical Pharmacology Evaluation

Aristolochic Acid-Induced Nephrotoxicity: Molecular Mechanisms and Potential Protective Approaches

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