title: Uremic toxins induce kidney fibrosis by activating intrarenal renin-angiotensin-aldosterone system associated epithelial-to-mesenchymal transition.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: School of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Chiao-Yin
authors.initials: CY
authors.lastname: Sun
authors.forename: Shih-Chung
authors.initials: SC
authors.lastname: Chang
authors.forename: Mai-Szu
authors.initials: MS
authors.lastname: Wu
mesh_terms: D000808:Angiotensinogen / Q000096:biosynthesis; D000818:Animals; D003408:Cresols / Q000633:toxicity*; D058750:Epithelial-Mesenchymal Transition; D005355:Fibrosis / Q000139:chemically induced*; D005786:Gene Expression Regulation; D007200:Indican / Q000633:toxicity*; D007668:Kidney / Q000473:pathology*; D007676:Kidney Failure, Chronic / Q000150:complications / Q000473:pathology; D007684:Kidney Tubules; D019808:Losartan / Q000494:pharmacology; D008297:Male; D051379:Mice; D008954:Models, Biological; D044140:Receptor, Angiotensin, Type 1 / Q000096:biosynthesis; D012083:Renin / Q000096:biosynthesis; D012084:Renin-Angiotensin System / Q000502:physiology*; D000071250:Snail Family Transcription Factors; D013463:Sulfuric Acid Esters / Q000633:toxicity*; D014157:Transcription Factors / Q000096:biosynthesis; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis; D014511:Uremia / Q000150:complications*
chemical_list: D003408:Cresols; D044140:Receptor, Angiotensin, Type 1; D000071250:Snail Family Transcription Factors; D013463:Sulfuric Acid Esters; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; D000808:Angiotensinogen; C408690:4-cresol sulfate; D012083:Renin; D019808:Losartan; D007200:Indican