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      Phenyl sulfate, indoxyl sulfate and p-cresyl sulfate decrease glutathione level to render cells vulnerable to oxidative stress in renal tubular cells

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          Abstract

          In chronic kidney disease patients, oxidative stress is generally associated with disease progression and pathogenesis of its comorbidities. Phenyl sulfate is a protein-bound uremic solute, which accumulates in chronic kidney disease patients, but little is known about its nature. Although many reports revealed that protein-bound uremic solutes induce reactive oxygen species production, the effects of these solutes on anti-oxidant level have not been well studied. Therefore, we examined the effects of protein-bound uremic solutes on glutathione levels. As a result, indoxyl sulfate, phenyl sulfate, and p-cresyl sulfate decreased glutathione levels in porcine renal tubular cells. Next we examined whether phenyl sulfate-treated cells becomes vulnerable to oxidative stress. In phenyl sulfate-treated cells, hydrogen peroxide induced higher rates of cell death than in control cells. Buthionine sulfoximine, which is known to decrease glutathione level, well mimicked the effect of phenyl sulfate. Finally, we evaluated a mixture of indoxyl sulfate, phenyl sulfate, and p-cresyl sulfate at concentrations comparable to the serum concentrations of hemodialysis patients, and we confirmed its decreasing effect on glutathione level. In conclusion, indoxyl sulfate, phenyl sulfate, and p-cresyl sulfate decrease glutathione levels, rendering the cells vulnerable to oxidative stress.

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          Serum indoxyl sulfate is associated with vascular disease and mortality in chronic kidney disease patients.

          As a major component of uremic syndrome, cardiovascular disease is largely responsible for the high mortality observed in chronic kidney disease (CKD). Preclinical studies have evidenced an association between serum levels of indoxyl sulfate (IS, a protein-bound uremic toxin) and vascular alterations. The aim of this study is to investigate the association between serum IS, vascular calcification, vascular stiffness, and mortality in a cohort of CKD patients. One-hundred and thirty-nine patients (mean +/- SD age: 67 +/- 12; 60% male) at different stages of CKD (8% at stage 2, 26.5% at stage 3, 26.5% at stage 4, 7% at stage 5, and 32% at stage 5D) were enrolled. Baseline IS levels presented an inverse relationship with renal function and a direct relationship with aortic calcification and pulse wave velocity. During the follow-up period (605 +/- 217 d), 25 patients died, mostly because of cardiovascular events (n = 18). In crude survival analyses, the highest IS tertile was a powerful predictor of overall and cardiovascular mortality (P = 0.001 and 0.012, respectively). The predictive power of IS for death was maintained after adjustment for age, gender, diabetes, albumin, hemoglobin, phosphate, and aortic calcification. The study presented here indicates that IS may have a significant role in the vascular disease and higher mortality observed in CKD patients.
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            Emerging biomarkers for evaluating cardiovascular risk in the chronic kidney disease patient: how do new pieces fit into the uremic puzzle?

            Premature cardiovascular disease (CVD), including stroke, peripheral vascular disease, sudden death, coronary artery disease, and congestive heart failure, is a notorious problem in patients with chronic kidney disease (CKD). Because the presence of CVD is independently associated with kidney function decline, it appears that the relationship between CKD and CVD is reciprocal or bidirectional, and that it is this association that leads to the vicious circle contributing to premature death. As randomized, placebo-controlled trials have so far been disappointing and unable to show a survival benefit of various treatment strategies, such a lipid-lowering, increased dialysis dose and normalization of hemoglobin, the risk factor profile seems to be different in CKD compared with the general population. Indeed, seemingly paradoxical associations between traditional risk factors and cardiovascular outcome in patients with advanced CKD have complicated our efforts to identify the real cardiovascular culprits. This review focuses on the many new pieces that need to be fit into the complicated puzzle of uremic vascular disease, including persistent inflammation, endothelial dysfunction, oxidative stress, and vascular ossification. Each of these is not only highly prevalent in CKD but also more strongly linked to CVD in these patients than in the general population. However, a causal relationship between these new markers and CVD in CKD patients remains to be established. Finally, two novel disciplines, proteomics and epigenetics, will be discussed, because these tools may be helpful in the understanding of the discussed vascular risk factors.
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              The uremic solute indoxyl sulfate induces oxidative stress in endothelial cells.

              Endothelial dysfunction and oxidative stress are matters of concern in patients with chronic renal failure (CRF). Uremic solutes retained in these patients could be involved in these processes. Notably, the protein-bound uremic solute indoxyl sulfate induces endothelial dysfunction in vitro, and has shown pro-oxidant effects. To demonstrate that indoxyl sulfate is a potential mediator of oxidative stress in endothelial cells in vitro. Indoxyl sulfate-induced oxidative stress in human umbilical vein endothelial cells (HUVEC) was studied by measuring reactive oxygen specie (ROS) production by cytofluorimetry, by analyzing the involvement of the pro-oxidative enzymes NAD(P)H oxidase, xanthine oxidase, and NO synthase, and by measuring the levels of the non-enzymatic antioxidant glutathione. We showed that indoxyl sulfate induced a significant production of ROS in HUVEC, with or without human serum albumin. We then investigated the role of pro-oxidative enzymes and measured the levels of the antioxidant glutathione. The NAD(P)H oxidase inhibitors, DPI, and apocynin, inhibited ROS production, whereas inhibitors of xanthine oxidase, NO synthase, and mitochondrial ROS had no effect. Interestingly, indoxyl sulfate strongly decreased the levels of glutathione, one of the most active antioxidant systems of the cell. In addition, the ROS production mediated by indoxyl sulfate was inhibited by the antioxidants vitamin C, vitamin E, and NAC. The uremic solute indoxyl sulfate enhances ROS production, increases NAD(P)H oxidase activity, and decreases glutathione levels in endothelial cells. Thus, indoxyl sulfate induces oxidative stress by modifying the balance between pro- and antioxidant mechanisms in endothelial cells.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Writing – original draft
                Role: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Writing – review & editing
                Role: ConceptualizationRole: Project administrationRole: SupervisionRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                23 February 2018
                2018
                : 13
                : 2
                : e0193342
                Affiliations
                [001]Pharmaceuticals & Agrochemicals Division, Kureha Corporation, Tokyo, Japan
                University of PECS Medical School, HUNGARY
                Author notes

                Competing Interests: All three authors are employees of Kureha Corporation. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

                Author information
                http://orcid.org/0000-0002-1782-2719
                Article
                PONE-D-17-41218
                10.1371/journal.pone.0193342
                5825083
                29474405
                584e9a74-5f35-4992-85bc-44657dbe8e4d
                © 2018 Edamatsu et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 22 November 2017
                : 8 February 2018
                Page count
                Figures: 11, Tables: 0, Pages: 14
                Funding
                Funded by: Kureha Corporation
                Award Recipient :
                This work was supported by Kureha Corporation. Kureha Corporation had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Biochemistry
                Peptides
                Glutathione
                Physical Sciences
                Chemistry
                Chemical Compounds
                Oxides
                Peroxides
                Hydrogen Peroxide
                Physical Sciences
                Chemistry
                Chemical Compounds
                Salts
                Sulfates
                Medicine and Health Sciences
                Nephrology
                Chronic Kidney Disease
                Biology and Life Sciences
                Cell Biology
                Oxidative Stress
                Biology and Life Sciences
                Cell Biology
                Cell Processes
                Cell Death
                Biology and Life Sciences
                Biochemistry
                Antioxidants
                Physical Sciences
                Materials Science
                Materials by Structure
                Mixtures
                Solutions
                Solutes
                Custom metadata
                All relevant data are within the paper.

                Uncategorized
                Uncategorized

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