title: Inhibitory effect of pravastatin on transforming growth factor beta1-inducible gene h3 expression in a rat model of chronic cyclosporine nephropathy.
abstract: OBJECTIVE
  Overexpression of transforming growth factor beta1-inducible gene h3 (betaig-h3) is associated with renal scarring in several models of renal disease. We investigated the inhibitory effect of pravastatin on betaig-h3 expression in a rat model of chronic cyclosporin A (CsA)-induced nephropathy.
  
  
  METHODS
  Adult Sprague Dawley rats kept on a low salt diet (0.05% sodium) were treated daily for 4 weeks with vehicle (olive oil, 1 ml/kg), CsA (15 mg/kg) or both CsA and pravastatin (20 mg/kg in drinking water). The effect of pravastatin on betaig-h3 expression was evaluated using in situ hybridization, immunohistochemistry, and immunoblotting. Functional parameters, histopathology (tubulointerstitial fibrosis, TIF, and arteriolopathy), and levels of transforming growth factor beta1 (TGF-beta1) and endothelial nitric oxide synthase were compared for the different treatment groups.
  
  
  RESULTS
  Co-administration of pravastatin significantly inhibited betaig-h3 mRNA production and gene expression within the tubulointerstitium of the CsA-treated kidneys, and this paralleled an attenuation of TIF (12.7 +/- 2.2 vs. 35.9 +/- 5.4%, p < 0.01 vs. CsA) and the expression of TGF-beta1 mRNA (279 +/- 40 vs. 719 +/- 85%, p < 0.01 vs. CsA). Pravastatin treatment reduced endothelial nitric oxide synthase protein levels and reversed the renal dysfunction caused by CsA. Neither CsA nor pravastatin affected total serum cholesterol or triglyceride levels in the treatment groups.
  
  
  CONCLUSIONS
  Pravastatin thus effectively abrogated the upregulation of betaig-h3 gene expression and associated TGF-beta1 production, and this was associated with attenuated TIF in this model of chronic CsA-induced nephropathy.
authors.affiliation: Department of Internal Medicine, Xenotransplantation Center, KangNam St. Mary's Hospital, Seoul, Korea.
authors.forename: Can
authors.initials: C
authors.lastname: Li
authors.forename: Sun Woo
authors.initials: SW
authors.lastname: Lim
authors.forename: Bum Soon
authors.initials: BS
authors.lastname: Choi
authors.forename: Suk Hee
authors.initials: SH
authors.lastname: Lee
authors.forename: Jung Ho
authors.initials: JH
authors.lastname: Cha
authors.forename: In San
authors.initials: IS
authors.lastname: Kim
authors.forename: Jin
authors.initials: J
authors.lastname: Kim
authors.forename: Chul Woo
authors.initials: CW
authors.lastname: Yang
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D016572:Cyclosporine; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects*; D007150:Immunohistochemistry; D007668:Kidney / Q000473:pathology; D008297:Male; D009400:Nephrosclerosis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D017035:Pravastatin / Q000494:pharmacology* / Q000627:therapeutic use; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D016212:Transforming Growth Factor beta / Q000187:drug effects*; D053773:Transforming Growth Factor beta1
chemical_list: D012333:RNA, Messenger; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D016572:Cyclosporine; D052250:Nitric Oxide Synthase Type III; D017035:Pravastatin