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. 2011 Jan;6(1):30-9.
doi: 10.2215/CJN.05340610. Epub 2010 Sep 28.

Indoxyl sulfate-induced endothelial dysfunction in patients with chronic kidney disease via an induction of oxidative stress

Mina Yu  1 , Young Ju Kim, Duk-Hee Kang
Affiliations

Indoxyl sulfate-induced endothelial dysfunction in patients with chronic kidney disease via an induction of oxidative stress

Mina Yu et al. Clin J Am Soc Nephrol. 2011 Jan.

Abstract

Background and objectives: Recent data suggest indoxyl sulfate (IS), one of the uremic toxins that accelerate the progression of chronic kidney disease (CKD), may also be responsible for vascular disease via an induction of oxidative stress. The role of IS in endothelial dysfunction in CKD and potential mechanisms of IS-induced endothelial dysfunction were investigated.

Design, setting, participants, & measurements: A prospective observational study in 40 CKD patients was performed. Flow-mediated endothelium-dependent vasodilatation (FMD) and its reaction time before and 24 weeks after an oral adsorbent of IS were evaluated. Plasma levels of IS and markers of oxidative stress were also measured. The proliferation, senescence, and production of nitric oxide and reactive oxygen species from human umbilical vein endothelial cells (HUVEC) were evaluated and the effect of antioxidants, N-acetylcysteine, rotenone, and apocynin was examined to explore the mechanism of IS-induced endothelial dysfunction.

Results: AST-120 treatment for 24 weeks resulted in a significant increase in FMD with a decrease in IS and oxidized/reduced glutathione ratio. The presence of diabetes and high-sensitivity C-reactive protein were the independent predictors for an improved FMD. IS induced a production of reactive oxygen species in HUVEC, and pretreatment with antioxidants ameliorated IS-induced inhibition of proliferation and nitric oxide production and inhibited a senescence of HUVEC.

Conclusions: IS may play an important role in endothelial dysfunction via generation of oxidative stress with an induction of endothelial senescence. AST-120 improved endothelial dysfunction in patients with CKD associated with a decrease in IS and a restoration of antioxidant reserve.

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Figures

Figure 1.
Figure 1.
Endothelial function before and after IS-lowering therapy. (A) FMD, (B) IRT of FMD, and (C) PRT of FMD were improved with AST-120 for 24 weeks in patients with CKD. Horizontal lines at the top, middle, and bottom of the boxes show the 75th, 50th, and 25th percentiles, and vertical lines above and below the boxes show the 90th and 10th percentiles, respectively. *P < 0.05 versus before AST-120.
Figure 2.
Figure 2.
Correlation between ΔIS and ΔFMD before and after AST-120.
Figure 3.
Figure 3.
Effect of IS on proliferation, senescence, and the production of NO and ROS from endothelial cells. IS induced a dose-dependent inhibition of proliferation (A), an increase in cell senescence (B), and a decrease in NO production (C) from a concentration of 0.25 mg/dl at 24 and 48 hours. IS-induced changes in HUVEC were blocked by probenecid (P). Data show the average of four separate experiments performed in duplicate. *P < 0.05 versus others at each time point, †P < 0.05 versus 0, 0.25 of IS and the conditions with probenecid. IS at the concentrations above 0.25 mg/dl also increased ROS generation from 10 minutes of stimulation (D). Hydrogen peroxide (0.1 mM) was used for positive control inducing oxidative stress in HUVEC. Data show the average of four separate experiments performed in duplicate. *P < 0.05 versus control (0 minutes), †P < 0.05 versus control and IS-containing conditions at 10 and 30 minutes.
Figure 4.
Figure 4.
IS-induced senescence of HUVEC. Representative photos of SA β-gal staining in control (A) and IS-stimulated cells (B, 2.5 mg/dl; C, 12.5 mg/dl).
Figure 5.
Figure 5.
Effect of antioxidants on IS-induced changes in proliferation, senescence, and NO production in HUVEC. Antioxidant, NAC (I + N), rotenone (I + R), or apocynin (I + A) ameliorated IS (0.25 mg/dl)–induced changes in cell proliferation, senescence, and NO production at 48 hours. Data show the average of six separate experiments performed in duplicate. *P < 0.05 versus others at each experiment.
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