title: Simvastatin Inhibits Epithelial-to-Mesenchymal Transition Through Induction of HO-1 in Cultured Renal Proximal Tubule Cells.
abstract: OBJECTIVE
  Studies have shown that simvastatin (SIM) inhibits epithelial-mesenchymal transition (EMT), a key step in fibrosis, and activates the anti-fibrotic heme oxygenase-1 (HO-1) gene in renal proximal tubule cells independent of its lipid-lowering. We tested the hypothesis that SIM inhibits EMT via HO-1-dependent suppression of reactive oxygen species (ROS) release.
  
  
  METHODS
  Renal proximal tubule cells were treated with either 10 μM SIM or 10 ng/ml transforming growth factor-β1 (TGFβ1) or with their combination and promoter activity of the alpha-smooth muscle actin (α-SMA) gene, stress fiber formation (markers of EMT), as well as ROS production were determined. HO-1 was manipulated via genetic and pharmacologic means.
  
  
  RESULTS
  SIM prevented TGFβ1-dependent EMT and ROS production. Inhibition/knockdown of HO-1 reversed, while induction/overexpression of HO-1 emulated beneficial effects of SIM.
  
  
  CONCLUSIONS
  SIM, via HO-1, suppresses TGFβ1-dependent ROS production and, hence, EMT. Further evaluation of the anti-fibrotic nature of SIM in the kidney would be useful in the treatment of chronic kidney disease.
authors.affiliation: Department of Internal Medicine, University of Mississippi Medical Center, Jackson, MS, U.S.A.
authors.forename: Jeb S
authors.initials: JS
authors.lastname: Clark
authors.affiliation: Department of Pediatrics, Division of Pediatric Nephrology, University of Mississippi Medical Center, Jackson, MS, U.S.A.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Carter
authors.affiliation: Department of Pediatrics, Division of Pediatric Nephrology, University of Mississippi Medical Center, Jackson, MS, U.S.A.
authors.forename: Mehul
authors.initials: M
authors.lastname: Dixit
authors.affiliation: Department of Pediatrics, Division of Pediatric Nephrology, University of Mississippi Medical Center, Jackson, MS, U.S.A. iarany@umc.edu.
authors.forename: Istvan
authors.initials: I
authors.lastname: Arany
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D017382:Reactive Oxygen Species / Q000378:metabolism; D019821:Simvastatin / Q000494:pharmacology*; D013552:Swine; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
chemical_list: D000924:Anticholesteremic Agents; D017382:Reactive Oxygen Species; D053773:Transforming Growth Factor beta1; D019821:Simvastatin; D051547:Heme Oxygenase-1
keywords: HO-1; Renal; fibrosis; protection; simvastatin