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Toxins 2018, 10(7), 280; https://doi.org/10.3390/toxins10070280

Indoxyl Sulfate, a Uremic Toxin, Stimulates Reactive Oxygen Species Production and Erythrocyte Cell Death Supposedly by an Organic Anion Transporter 2 (OAT2) and NADPH Oxidase Activity-Dependent Pathways

1
Graduate Program in Health Sciences, School of Medicine, Pontifícia Universidade Católica do Paraná; Curitiba-PR 80215-901, Brasilien
2
Department of Basic Pathology, Federal University of Paraná, Curitiba-PR 80060-000, Brazil
3
Renal Research Institute, New York, NY 10065, USA
*
Author to whom correspondence should be addressed.
Received: 18 May 2018 / Revised: 29 June 2018 / Accepted: 2 July 2018 / Published: 5 July 2018
(This article belongs to the Section Uremic Toxins)
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Abstract

It is hypothesized that the uremic toxin indoxyl sulfate (IS) plays a role in the pathogenesis of renal anemia. To further explore that hypothesis, we examined the effects of IS on reactive oxygen species (ROS) production, levels of reduced glutathione (GSH), and erythrocyte death (eryptosis) in red blood cells (RBC) from healthy controls (CON-RBC) and hemodialyzed patients (HD-RBC), respectively. RBC were incubated either in either TRIS-Glc-BSA buffer or IS at concentrations of 0.01, 0.09, and 0.17 mM, respectively. We measured ROS generation (expressed as % of DCFH-DA positive RBC), eryptosis (expressed as % of annexin-V positive RBC), and GSH levels after 6, 12, and 24 h. When incubated in buffer, ROS production was approximately seven-fold higher at all time points HD-RBC when compared to CON-RBC. Incubation with IS increased ROS production in CON-RBS dose-dependently up to 10-fold. Eryptosis in buffer-incubated HD-RBC was up to seven-fold higher as compared to COB-RBC. Incubation of CON-RBC with IS increased the eryptosis rate dose-dependently up to 6-fold. Pretreatment of CON-RBC with the organic anion transporter 2 (OAT2) specific inhibitor ketoprofen or with NADPH oxidase inhibitor diphenyleneiodonium-Cl blunted the IS effect on both ROS production and eryptosis induction. While GSH levels in HD-RBC were reduced when compared to CON-RBC, they were not affected by IS incubation. In summary, IS increases ROS generation and eryptosis in CON-RBC by an activity dependent of the IS influx through OAT2, and NADPH oxidase activity-dependent, and a GSH-independent mechanism. These findings lend support to a putative role of IS in the pathogenesis of renal anemia. View Full-Text
Keywords: chronic kidney disease; indoxyl sulfate; eryptosis; oxidative stress chronic kidney disease; indoxyl sulfate; eryptosis; oxidative stress
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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Dias, G.F.; Bonan, N.B.; Steiner, T.M.; Tozoni, S.S.; Rodrigues, S.; Nakao, L.S.; Kuntsevich, V.; Pecoits Filho, R.; Kotanko, P.; Moreno-Amaral, A.N. Indoxyl Sulfate, a Uremic Toxin, Stimulates Reactive Oxygen Species Production and Erythrocyte Cell Death Supposedly by an Organic Anion Transporter 2 (OAT2) and NADPH Oxidase Activity-Dependent Pathways. Toxins 2018, 10, 280.

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