title: Statin monotherapy attenuates renal injury in a salt-sensitive hypertension model of renal disease.
abstract: BACKGROUND
  Several salutary biological effects of statins have been described. We sought to investigate more closely the anti-inflammatory and antiproliferative effects of simvastatin (SIMV) in a model of hypertension and progressive renal disease, as well as its effects on the cyclin-cdk inhibitors p21 and p27.
  
  
  METHODS
  Munich-Wistar rats received the nitric oxide (NO) synthase inhibitor L-NAME (25 mg/kg/day p.o.) for 20 days accompanied by a high-salt diet (HS, 3% Na) and then were kept on HS for 60 days. Animals were then divided into two groups: vehicle (VH) or SIMV 2 mg/kg/day p.o. Albuminuria and tail-cuff pressure were determined at 30 and 60 days. RT-PCR was done to assess renal expression of TGF-beta1, collagen I and III, fibronectin, p27, p21 and monocyte chemoattractant protein-1 (MCP-1). Renal protein expression was assessed by Western blot (proliferating cell nuclear antigen (PCNA)) and immunostaining (macrophage, lymphocyte, PCNA).
  
  
  RESULTS
  SIMV did not prevent the development of severe hypertension or albuminuria. SIMV-treated animals had less severe renal interstitial inflammation and cell proliferation. MCP-1 expression was significantly diminished in the SIMV-treated animals (55.4 +/- 7.3 vs. 84.4 +/- 8.2 OD, p = 0.02). mRNA renal expression for p27 and TGF-beta did not change between groups, but p21 mRNA renal expression, highly induced in this model, significantly decreased with SIMV treatment (31.6 +/- 6.6 vs. 50.2 +/- 5.8 OD, p < 0.05). The interstitial fibrosis score significantly decreased with SIMV (2.46 +/- 0.40 vs. 4.07 +/- 0.38%, p < 0.01), which was confirmed by a decrease in renal collagen I and fibronectin expression. Serum cholesterol level did not change with SIMV.
  
  
  CONCLUSIONS
  SIMV attenuated interstitial fibrosis associated with this model of hypertensive renal disease. The mechanism involved MCP-1 downregulation. SIMV treatment was also associated with a p21 downregulation in the kidney, which might be involved in the protection of renal scarring.
authors.affiliation: Internal Medicine, Renal Division, University of São Paulo, São Paulo, Brazil. josemvjr@usp.br
authors.forename: J M
authors.initials: JM
authors.lastname: Vieira
authors.forename: L T
authors.initials: LT
authors.lastname: Rodrigues
authors.forename: E
authors.initials: E
authors.lastname: Mantovani
authors.forename: H
authors.initials: H
authors.lastname: Dellê
authors.forename: A L
authors.initials: AL
authors.lastname: Mattar
authors.forename: D M A C
authors.initials: DM
authors.lastname: Malheiros
authors.forename: I L
authors.initials: IL
authors.lastname: Noronha
authors.forename: C K
authors.initials: CK
authors.lastname: Fujihara
authors.forename: R
authors.initials: R
authors.lastname: Zatz
mesh_terms: D000419:Albuminuria / Q000276:immunology / Q000473:pathology; D000818:Animals; D002455:Cell Division; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005109:Extracellular Matrix / Q000502:physiology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D006977:Hypertension, Renal / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology*; D008214:Lymphocytes / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D019821:Simvastatin / Q000494:pharmacology*; D012965:Sodium Chloride / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000235:genetics
chemical_list: C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D050760:Cyclin-Dependent Kinase Inhibitor p27; D012965:Sodium Chloride; D019821:Simvastatin; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester