Dynamic modeling of Nrf2 pathway activation in liver cells after toxicant exposure

Cells are exposed to oxidative stress and reactive metabolites every day. The Nrf2 signaling pathway responds to oxidative stress by upregulation of antioxidants like glutathione (GSH) to compensate the stress insult and re-establish homeostasis. Although mechanisms describing the interaction betwee...

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Bibliographic Details
Published in:Scientific reports Vol. 12; no. 1; pp. 7336 - 10
Main Authors: Hiemstra, Steven, Fehling-Kaschek, Mirjam, Kuijper, Isoude A., Bischoff, Luc J. M., Wijaya, Lukas S., Rosenblatt, Marcus, Esselink, Jeroen, van Egmond, Allard, Mos, Jornt, Beltman, Joost B., Timmer, Jens, van de Water, Bob, Kaschek, Daniel
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 05.05.2022
Nature Publishing Group
Nature Portfolio
Subjects:
631/553/1833
631/553/2695
639/705/794
Antioxidants
Cell activation
Confocal microscopy
Diclofenac
Diethyl maleate
Glutathione
Glutathione - metabolism
Green fluorescent protein
Hep G2 Cells
Hepatocytes
Hepatocytes - metabolism
Homeostasis
Humanities and Social Sciences
Humans
Kelch-Like ECH-Associated Protein 1 - metabolism
Liver
Liver - metabolism
Mathematical models
Metabolites
multidisciplinary
NF-E2-Related Factor 2 - metabolism
Omeprazole
Ordinary differential equations
Oxidative Stress
Science
Science (multidisciplinary)
Signal transduction
siRNA
Toxicants
ISSN:2045-2322, 2045-2322
Online Access:Get full text
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Summary:Cells are exposed to oxidative stress and reactive metabolites every day. The Nrf2 signaling pathway responds to oxidative stress by upregulation of antioxidants like glutathione (GSH) to compensate the stress insult and re-establish homeostasis. Although mechanisms describing the interaction between the key pathway constituents Nrf2, Keap1 and p62 are widely reviewed and discussed in literature, quantitative dynamic models bringing together these mechanisms with time-resolved data are limited. Here, we present an ordinary differential equation (ODE) based dynamic model to describe the dynamic response of Nrf2, Keap1, Srxn1 and GSH to oxidative stress caused by the soft-electrophile diethyl maleate (DEM). The time-resolved data obtained by single-cell confocal microscopy of green fluorescent protein (GFP) reporters and qPCR of the Nrf2 pathway components complemented with siRNA knock down experiments, is accurately described by the calibrated mathematical model. We show that the quantitative model can describe the activation of the Nrf2 pathway by compounds with a different mechanism of activation, including drugs which are known for their ability to cause drug induced liver-injury (DILI) i.e., diclofenac (DCF) and omeprazole (OMZ). Finally, we show that our model can reveal differences in the processes leading to altered activation dynamics amongst DILI inducing drugs.
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ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-022-10857-x