, Volume 16, Issue 3, pp 609–624

In acute kidney injury, indoxyl sulfate impairs human endothelial progenitor cells: modulation by statin

  • Vin-Cent Wu
  • Guang-Huar Young
  • Po-Hsun Huang
  • Shyh-Chyi Lo
  • Kuo-Chuan Wang
  • Chiao-Yin Sun
  • Chan-Jung Liang
  • Tao-Ming Huang
  • Jou-Han Chen
  • Fan-Chi Chang
  • Yuh-Lien Chen
  • Yih-Shing Kuo
  • Jin-Bor Chen
  • Jaw-Wen Chen
  • Yung-Ming Chen
  • Wen-Jo Ko
  • Kwan-Dun Wu
  • The NSARF group
Original Paper


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 × 10−4M vs. 0.02 ± 0.02 × 10−4M, 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.


Indoxyl sulfate Statin Endothelial nitric oxide synthase Endothelial progenitor cells Autophagy 



Acute kidney injury






Chronic kidney disease


Activated caspase 3




DNA fluorochrome 4′-6-diamidine-2-phenyl indole


Dichlorofluorescin diacetate


Endothelial nitric oxide synthase


Endothelial progenitor cells


End stage renal disease


Fluorescein isothiocyanate


Generalized additive model


Intercellular adhesion molecule 1


Indoxyl sulfate


Light Chain 3


3-(4,5-cimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide




Nitric oxide


Reactive nitrogen species


National Taiwan University Hospital Study Group on Acute Renal Failure


Organic anion transporter


Reactive oxygen species


Sodium nitroprusside




Transforming growth factor


Terminal deoxyribonucleotidyl transferase (TDT)-mediated dUTP-digoxigenin nick end labeling


Vascular cell adhesion molecule


Von Willebrand factor

Supplementary material

10456_2013_9339_MOESM1_ESM.docx (2.7 mb)
Supplementary material 1 (DOCX 2727 kb)


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Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  • Vin-Cent Wu
    • 1
  • Guang-Huar Young
    • 2
  • Po-Hsun Huang
    • 3
  • Shyh-Chyi Lo
    • 4
  • Kuo-Chuan Wang
    • 5
  • Chiao-Yin Sun
    • 6
  • Chan-Jung Liang
    • 7
  • Tao-Ming Huang
    • 8
  • Jou-Han Chen
    • 1
  • Fan-Chi Chang
    • 9
  • Yuh-Lien Chen
    • 7
  • Yih-Shing Kuo
    • 10
  • Jin-Bor Chen
    • 11
  • Jaw-Wen Chen
    • 3
  • Yung-Ming Chen
    • 1
  • Wen-Jo Ko
    • 2
  • Kwan-Dun Wu
    • 1
  • The NSARF group
  1. 1.Department of Internal MedicineNational Taiwan University HospitalTaipeiTaiwan
  2. 2.Department of SurgeryNational Taiwan University HospitalTaipeiTaiwan
  3. 3.Division of Cardiology, Department of Internal MedicineTaipei Veterans General HospitalTaipeiTaiwan
  4. 4.Department of Laboratory MedicineNational Taiwan University HospitalTaipeiTaiwan
  5. 5.Department of NeurologyNational Taiwan University HospitalTaipeiTaiwan
  6. 6.Division of NephrologyChang Gung Memorial HospitalKeelungTaiwan
  7. 7.Department of Anatomy and Cell Biology, College of MedicineNational Taiwan University HospitalTaipeiTaiwan
  8. 8.Yun-Lin BranchNational Taiwan University HospitalTaipeiTaiwan
  9. 9.Chu-Tung BranchNational Taiwan University HospitalTaipeiTaiwan
  10. 10.Bei-Hu branchNational Taiwan University HospitalTaipeiTaiwan
  11. 11.Division of NephrologyChang Gung Memorial HospitalKaohsiungTaiwan

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