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

Research output: Contribution to journalArticle

58 Citations (Scopus)

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 × 10-4M 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.

Original languageEnglish
Pages (from-to)609-624
Number of pages16
JournalAngiogenesis
Volume16
Issue number3
DOIs
Publication statusPublished - Jul 2013
Externally publishedYes

Keywords

  • Autophagy
  • Endothelial nitric oxide synthase
  • Endothelial progenitor cells
  • Indoxyl sulfate
  • Statin

ASJC Scopus subject areas

  • Cancer Research
  • Physiology
  • Clinical Biochemistry

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  • Cite this

    Wu, V. C., Young, G. H., Huang, P. H., Lo, S. C., Wang, K. C., Sun, C. Y., Liang, C. J., Huang, T. M., Chen, J. H., Chang, F. C., Chen, Y. L., Kuo, Y. S., Chen, J. B., Chen, J. W., Chen, Y. M., Ko, W. J., & Wu, K. D. (2013). In acute kidney injury, indoxyl sulfate impairs human endothelial progenitor cells: Modulation by statin. Angiogenesis, 16(3), 609-624. https://doi.org/10.1007/s10456-013-9339-8