Role of indoleamine 2,3-dioxygenase in ischemia-reperfusion injury of renal tubular epithelial cells.

Content Provider	Europe PMC
Author	Eleftheriadis, Theodoros Pissas, Georgios Golfinopoulos, Spyridon Liakopoulos, Vassilios Stefanidis, Ioannis
Copyright Year	2021
Abstract	The present study evaluated indoleamine 2,3-dioxygenase 1 (IDO) kinetics and how it affects cell survival during the two distinct phases of ischemia-reperfusion (I-R) injury. Primary renal proximal tubular epithelial cells (RPTECs) were cultured under anoxia or reoxygenation with or without the IDO inhibitor 1-DL-methyltryptophan, the aryl-hydrocarbon receptor (AhR) inhibitor CH223191 or the ferroptosis inhibitor α-tocopherol. Using cell imaging, colorimetric assays, PCR and western blotting, it was demonstrated that IDO was upregulated and induced apoptosis during anoxia. The related molecular pathway entails tryptophan degradation, general control non-derepressible-2 kinase (GCN2K) activation, increased level of phosphorylated eukaryotic translation initiation factor 2α, activating transcription factor (ATF)4, ATF3, C/EBP homologous protein, phosphorylated p53, p53, Bax, death receptor-5 and eventually activated cleaved caspase-3. Reoxygenation also upregulated IDO, which, in this case, induced ferroptosis. The related molecular pathway encompasses kynurenine production, AhR activation, cytochrome p450 enzymes increase, reactive oxygen species generation and eventually ferroptosis. In conclusion, in RPTECs, both anoxia and reoxygenation upregulated IDO, which in turn induced GCN2K-mediated apoptosis and AhR-mediated ferroptosis. Since both phases of I-R injury share IDO upregulation as a common point, its inhibition may prove a useful therapeutic strategy for preventing or attenuating I-R injury.
ISSN	17912997
Journal	Molecular Medicine Reports
Volume Number	23
PubMed Central reference number	PMC8097759
Issue Number	6
PubMed reference number	33899121
e-ISSN	17913004
DOI	10.3892/mmr.2021.12111
Language	English
Publisher	D.A. Spandidos
Publisher Date	2021-04-26
Access Restriction	Open
Rights License	This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. Copyright: © Eleftheriadis et al.
Subject Keyword	ischemia-reperfusion indoleamine 2,3-dioxygenase apoptosis ferroptosis general control non-derepressible-2 kinase aryl-hydrocarbon receptor
Content Type	Text
Resource Type	Article
Subject	Genetics Molecular Biology Biochemistry Cancer Research Molecular Medicine Oncology