Does indoxyl sulfate, a uraemic toxin, have direct effects on cardiac fibroblasts and myocytes?

Eur Heart J. 2010 Jul;31(14):1771-9. doi: 10.1093/eurheartj/ehp574. Epub 2010 Jan 4.


Aims: Indoxyl sulfate (IS) is a uraemic toxin found at high concentration in patients with chronic kidney disease (CKD) co-morbid with chronic heart failure (CHF). The aim of this study was to determine direct effects of IS on cardiac cells as well as the pro-inflammatory effect of IS.

Methods and results: Indoxyl sulfate significantly increased neonatal rat cardiac fibroblast collagen synthesis (by 145.7% vs. control, P < 0.05) and myocyte hypertrophy (by 134.5% vs. control, P < 0.001) as determined by (3)H-proline or (3)H-leucine incorporation, respectively. Indoxyl sulfate stimulated tumour necrosis factor-alpha, interleukin-6 (IL-6), and IL-1beta mRNA expression in THP-1 cells as quantified by RT-PCR. Both p38 (RWJ-67657) and MEK1/2 (U0126) inhibitors suppressed all these effects by IS. Furthermore, western blot analysis showed that IS activated mitogen-activated protein kinase (MAPK) (p38, p42/44) and nuclear factor-kappa B (NFkappaB) pathways. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay showed that IS exerted its effects without affecting cell viability.

Conclusion: This study has, for the first time, demonstrated that IS has pro-fibrotic, pro-hypertrophic, and pro-inflammatory effects, indicating that IS might play an important role in adverse cardiac remodelling mediated via activation of the p38 MAPK, p42/44 MAPK, and NFkappaB pathways. Targeting reduction of IS and/or the pathways it activates may represent a novel therapeutic approach to the management of CHF with concomitant CKD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Cardiomyopathy, Hypertrophic / etiology
  • Cardiomyopathy, Hypertrophic / pathology
  • Cell Survival
  • Cells, Cultured
  • Cytokines / metabolism
  • Dose-Response Relationship, Drug
  • Fibroblasts / drug effects*
  • Indican / administration & dosage
  • Indican / pharmacology*
  • Kidney Failure, Chronic / etiology
  • Kidney Failure, Chronic / pathology
  • Myocytes, Cardiac / drug effects*
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Toxins, Biological / administration & dosage
  • Toxins, Biological / pharmacology*


  • Cytokines
  • RNA, Messenger
  • Toxins, Biological
  • Indican