title: Simvastatin attenuates renal inflammation, tubular transdifferentiation and interstitial fibrosis in rats with unilateral ureteral obstruction.
abstract: BACKGROUND
  The pleiotropic actions of statins have been largely explored. These drugs have been tested in several models of progressive renal disease, most of them accompanied by hypertension. We sought to investigate more closely the effects of simvastatin on renal interstitial fibrosis due to unilateral ureteral obstruction (UUO).
  
  
  METHODS
  Munich-Wistar rats were submitted to UUO and studied after 14 days. Animals were divided into two groups: vehicle (VH) or simvastatin (SIMV) 2 mg/kg b.i.d. by gavage. At sacrifice kidneys were harvested for morphology, mRNA and protein analysis. RT-PCR was done to assess expression of collagen I and III, fibronectin, MCP-1, TGF-beta1 and bFGF. Protein expression was assessed by western blot (TGF-beta) and immunostaining (macrophage, lymphocyte, PCNA, vimentin and alpha-smooth muscle actin). Contralateral kidneys (CL) were used as controls.
  
  
  RESULTS
  SIMV-treated animals had less severe renal inflammation. MCP-1 was markedly expressed in obstructed kidneys and diminished with SIMV (48.9+/- 2.5 vs 64.3+/-3.1 OD in VH, P<0.01). Interstitial fibrosis (IF) was significantly attenuated with SIMV (8.2+/-1.3 vs 13.2+/-0.6%, P<0.01 SIMV vs VH), which was confirmed by a decrease in collagen I and fibronectin renal expression. Vimentin, a marker of dedifferentiation, was expressed in tubular cells of VH and decreased with SIMV treatment. alpha-SMA, a marker of myofibroblast-type cells, was increased in renal interstitium of VH rats and SIMV significantly reduced its expression. PCNA was increased in the UUO kidneys, but SIMV did not decrease tubular or interstitial proliferating cells. TGF-beta1, which was highly induced in the obstructed kidneys, decreased at the post-transcriptional level with SIMV treatment (5.35+/-0.75 vs 13.10+/-2.9 OD in VH, P<0.05). bFGF mRNA was also overexpressed in the obstructed kidneys, although SIMV treatment did not significantly decrease its expression.
  
  
  CONCLUSIONS
  SIMV had an evident protective effect on renal interstitial inflammation and fibrosis. It is conceivable that by attenuating inflammation, SIMV prevented tubular activation and transdifferentiation, two processes largely involved in the renal fibrosis of the UUO model.
authors.affiliation: Internal Medicine, Renal Division, University of São Paulo, São Paulo, Brazil. josemvjr@usp.br
authors.forename: José Mauro
authors.initials: JM
authors.lastname: Vieira
authors.forename: Eduardo
authors.initials: E
authors.lastname: Mantovani
authors.forename: Leonardo Tavares
authors.initials: LT
authors.lastname: Rodrigues
authors.forename: Humberto
authors.initials: H
authors.lastname: Dellê
authors.forename: Irene Lourdes
authors.initials: IL
authors.lastname: Noronha
authors.forename: Clarice Kazue
authors.initials: CK
authors.lastname: Fujihara
authors.forename: Roberto
authors.initials: R
authors.lastname: Zatz
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D018932:Chemokine CCL2 / Q000378:metabolism; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D005355:Fibrosis / Q000517:prevention & control; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D007684:Kidney Tubules / Q000187:drug effects* / Q000473:pathology; D008297:Male; D009395:Nephritis, Interstitial / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D019821:Simvastatin / Q000627:therapeutic use*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014517:Ureteral Obstruction / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D000199:Actins; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D005353:Fibronectins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D018809:Proliferating Cell Nuclear Antigen; D016212:Transforming Growth Factor beta; D016222:Fibroblast Growth Factor 2; D003094:Collagen; D019821:Simvastatin