title: Statin upregulates the expression of klotho, an anti-aging gene, in experimental cyclosporine nephropathy.
abstract: BACKGROUND
  We recently reported that long-term cyclosporine (CsA)-induced oxidative stress is associated with decreased expression of klotho, an anti-aging gene. This study evaluated whether the antioxidant effect of statin might upregulate klotho expression in CsA-induced renal injury.
  
  
  METHODS
  Two separate experiments were performed. First, the dose-dependent effect of statin on klotho expression was evaluated in normal mouse kidneys. Second, the effect of statin on klotho expression was evaluated in experimental chronic CsA nephropathy in mice. We performed immunohistochemistry and immunoblotting for klotho, Forkhead box O transcription factors [FoxOs; phosphorylated FoxO1 (p-FoxO1) and FoxO3a (p-FoxO3a)] and their target molecules, manganese superoxide dismutase (MnSOD), Bim and hemeoxygenase-1.
  
  
  RESULTS
  Statin treatment upregulated klotho expression in a dose-dependent manner in the normal mouse kidney and alleviated the decrease in klotho expression in kidneys exhibiting CsA nephropathy. CsA administration increased p-FoxO1 expression and decreased p-FoxO3a expression, whereas concurrent statin treatment reversed these changes, increased the expression of the antioxidant enzymes MnSOD and hemeoxygenase-1 and decreased the expression of the pro-apoptotic protein Bim.
  
  
  CONCLUSIONS
  Statin-mediated upregulation of klotho expression and differential regulation of FoxO expression promote resistance to CsA-induced oxidative stress.
authors.affiliation: Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Hye Eun
authors.initials: HE
authors.lastname: Yoon
authors.forename: Sun Woo
authors.initials: SW
authors.lastname: Lim
authors.forename: Shang Guo
authors.initials: SG
authors.lastname: Piao
authors.forename: Ji-Hyun
authors.initials: JH
authors.lastname: Song
authors.forename: Jin
authors.initials: J
authors.lastname: Kim
authors.forename: Chul Woo
authors.initials: CW
authors.lastname: Yang
mesh_terms: D000375:Aging / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D016572:Cyclosporine; D005966:Glucuronidase / Q000378:metabolism*; D007166:Immunosuppressive Agents; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D007674:Kidney Diseases / Q000139:chemically induced / Q000378:metabolism*; D000090265:Klotho Proteins; D008297:Male; D051379:Mice; D017035:Pravastatin / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
chemical_list: D007166:Immunosuppressive Agents; D016572:Cyclosporine; D005966:Glucuronidase; D000090265:Klotho Proteins; D017035:Pravastatin