Uremic toxins induce kidney fibrosis by activating intrarenal renin-angiotensin-aldosterone system associated epithelial-to-mesenchymal transition

PLoS One. 2012;7(3):e34026. doi: 10.1371/journal.pone.0034026. Epub 2012 Mar 30.


Background: Uremic toxins are considered to have a determinant pathological role in the progression of chronic kidney disease. The aim of this study was to define the putative pathological roles of the renal renin-angiotensin-aldosterone system (RAAS) and renal tubular epithelial-to-mesenchymal transition (EMT) in kidney fibrosis induced by (indoxyl sulfate) IS and (p-cresol sulfate) PCS.

Methods: Mouse proximal renal tubular cells (PKSV-PRs) treated with IS or PCS were used. Half-nephrectomized B-6 mice were treated with IS or PCS for 4 weeks. In the losartan treatment study, the study animal was administrated with IS+losartan or PCS+losartan for 4 weeks.

Results: IS and PCS significantly activated the intrarenal RAAS by increasing renin, angiotensinogen, and angiotensin 1 (AT1) receptor expression, and decreasing AT2 receptor expression in vitro and in vivo. IS and PCS significantly increased transforming growth factor-β1 (TGF-β1) expression and activated the TGF-β pathway by increasing Smad2/Smad2-P, Smad3/Smad3-P, and Smad4 expression. The expression of the EMT-associated transcription factor Snail was increased by IS and PCS treatment. IS and PCS induced the phenotype of EMT-like transition in renal tubules by increasing the expression of fibronectin and α-smooth muscle actin and decreasing the expression of E-cadherin. Losartan significantly attenuated the expression of TGF-β1 and Snail, and decreased kidney fibrosis induced by IS and PCS in vivo.

Conclusion: Activating the renal RAAS/TGF-β pathway has an important pathological role in chronic kidney injury caused by IS and PCS. IS and PCS may increase Snail expression and induce EMT-like transition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensinogen / biosynthesis
  • Animals
  • Cresols / toxicity*
  • Epithelial-Mesenchymal Transition
  • Fibrosis / chemically induced*
  • Gene Expression Regulation*
  • Indican / toxicity*
  • Kidney / pathology*
  • Kidney Failure, Chronic / complications
  • Kidney Failure, Chronic / pathology
  • Kidney Tubules
  • Losartan / pharmacology
  • Male
  • Mice
  • Models, Biological
  • Receptor, Angiotensin, Type 1 / biosynthesis
  • Renin / biosynthesis
  • Renin-Angiotensin System / physiology*
  • Snail Family Transcription Factors
  • Sulfuric Acid Esters / toxicity*
  • Transcription Factors / biosynthesis
  • Transforming Growth Factor beta1 / biosynthesis
  • Uremia / complications*


  • Cresols
  • Receptor, Angiotensin, Type 1
  • Snail Family Transcription Factors
  • Sulfuric Acid Esters
  • Transcription Factors
  • Transforming Growth Factor beta1
  • Angiotensinogen
  • 4-cresol sulfate
  • Renin
  • Losartan
  • Indican