title: In acute kidney injury, indoxyl sulfate impairs human endothelial progenitor cells: modulation by statin.
abstract: Renal ischemia rapidly mobilizes endothelial progenitor cells (EPCs), which provides renoprotection in acute kidney injury (AKI). Indoxyl sulfate (IS) is a protein-binding uremic toxin with a potential role in endothelial injury. In this study, we examined the effects and mechanisms of action of IS on EPCs in AKI. Forty-one consecutive patients (26 male; age, 70.1 ± 14.1 years) diagnosed with AKI according to the AKIN criteria were enrolled. The AKI patients had higher serum IS levels than patients with normal kidney function (1.35 ± 0.94 × 10(-4)M vs. 0.02 ± 0.02 × 10(-4)M, P < 0.01). IS levels were negatively correlated to the number of double-labeled (CD34(+)KDR(+)) circulating EPCs (P < 0.001). After IS stimulation, the cells displayed decreased expression of phosphorylated endothelial nitric oxide (NO) synthase, vascular cell adhesion molecule-1, increased reactive oxygen species, decreased proliferative capacity, increased senescence and autophagy, as well as decreased migration and angiogenesis. These effects of IS on EPCs were reversed by atorvastatin. Further, exogenous administration of IS significantly reduced EPC number in Tie2-GFP transgenic mice and attenuated NO signaling in aortic and kidney arteriolar endothelium after kidney ischemia-reperfusion injury in mice, and these effects were restored by atorvastatin. Our results are the first to demonstrate that circulating IS is elevated in AKI and has direct effects on EPCs via NO-dependent mechanisms both in vitro and in vivo. Targeting the IS-mediated pathways by NO-releasing statins such as atorvastatin may preempt disordered vascular wall pathology, and represent a novel EPC-rescued approach to impaired neovascularization after AKI.
authors: Department of Internal Medicine, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei 100, Taiwan. q91421028@ntu.edu.tw
authors: Vin-Cent
authors: VC
authors: Wu
authors: Guang-Huar
authors: GH
authors: Young
authors: Po-Hsun
authors: PH
authors: Huang
authors: Shyh-Chyi
authors: SC
authors: Lo
authors: Kuo-Chuan
authors: KC
authors: Wang
authors: Chiao-Yin
authors: CY
authors: Sun
authors: Chan-Jung
authors: CJ
authors: Liang
authors: Tao-Ming
authors: TM
authors: Huang
authors: Jou-Han
authors: JH
authors: Chen
authors: Fan-Chi
authors: FC
authors: Chang
authors: Yuh-Lien
authors: YL
authors: Chen
authors: Yih-Shing
authors: YS
authors: Kuo
authors: Jin-Bor
authors: JB
authors: Chen
authors: Jaw-Wen
authors: JW
authors: Chen
authors: Yung-Ming
authors: YM
authors: Chen
authors: Wen-Jo
authors: WJ
authors: Ko
authors: Kwan-Dun
authors: KD
authors: Wu
mesh_terms: D058186:Acute Kidney Injury / Q000188:drug therapy*; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D000069059:Atorvastatin; D015153:Blotting, Western; D002499:Centrifugation, Density Gradient; D042783:Endothelial Cells / Q000187:drug effects* / Q000502:physiology; D005260:Female; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000187:drug effects*; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007200:Indican / Q000097:blood / Q000633:toxicity*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013234:Stem Cells / Q000187:drug effects* / Q000502:physiology; D013624:Taiwan; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D006538:Heptanoic Acids; D011758:Pyrroles; D017382:Reactive Oxygen Species; D019010:Vascular Cell Adhesion Molecule-1; D000069059:Atorvastatin; D052250:Nitric Oxide Synthase Type III; D007200:Indican