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


METHODS
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.
Yu
Mina
M
Division of Nephrology, Department of Internal Medicine, Ewha Womans University School of Medicine, Seoul, Korea.
Kim
Young Ju
YJ
Kang
Duk-Hee
DH
D000328:Adult; D002244:Carbon / Q000494:pharmacology; D002478:Cells, Cultured; D002908:Chronic Disease; D042783:Endothelial Cells / Q000187:drug effects* / Q000502:physiology; D005260:Female; D006801:Humans; D007200:Indican / Q000097:blood / Q000633:toxicity*; D007674:Kidney Diseases / Q000150:complications / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000096:biosynthesis; D018384:Oxidative Stress; D010087:Oxides / Q000494:pharmacology; D011446:Prospective Studies
D010087:Oxides; D009569:Nitric Oxide; D002244:Carbon; C040896:AST 120; D007200:Indican