title: Nephroprotective effect of the HMG-CoA-reductase inhibitor cerivastatin in a mouse model of progressive renal fibrosis in Alport syndrome.
abstract: BACKGROUND
  Alport syndrome is caused by mutations in genes encoding for the alpha3, alpha4 or alpha5 chain of type IV collagen leading to excessive production of fibrotic tissue and end-stage renal failure. HMG-CoA-reductase-inhibitors exhibit pleiotropic effects by which they modulate the production of connective tissue. The aim of this study was to examine the anti-fibrotic effect of the HMG-CoA-reductase-inhibitor, cerivastatin, in COL4A3 knockout mice, an animal model of Alport syndrome with progressive renal fibrosis.
  
  
  METHODS
  Forty homozygous COL4A3 knockout mice received cerivastatin, starting 28 or 49 days after birth. Mice were sacrificed at day 52 or 66 after birth. Immunohistochemistry against laminin and fibronectin was performed. Inflammatory cell infiltration was determined by F4/80- and CD3-staining. Myofibroblasts were identified by an alpha-smooth muscle actin staining. Expression of the profibrotic cytokines, TGF-beta1 and CTGF, were determined by immunoblot.
  
  
  RESULTS
  The lifespan of treated COL4A3 knockout mice was increased by 28% compared with untreated animals (71+/-6 vs 91+/-9 days, P<0.01). Early cerivastatin treatment reduced cholesterol levels (113+/-13 vs 141+/-19 mmol/l in untreated animals, P<0.05) and serum urea (164 vs 235 mmol/l, day 66, P<0.05). Treatment also decreased proteinuria (5.5 vs 12 g/l at day 66, P<0.05). Deposition of laminin and fibronectin, expression of TGF-beta and CTGF was reduced. Infiltration of T-cells and macrophages as well as myofibroblasts appeared to be reduced in kidneys from cerivastatin-treated mice.
  
  
  CONCLUSIONS
  Cerivastatin prolongs the lifespan of COL4A3 knockout mice, reduces proteinuria and delays uraemia. These effects are associated with decreased renal fibrosis and a reduction of inflammatory cell infiltration.
authors.affiliation: Department of Internal Medicine I, Cologne General Hospital, Merheim Medical Center, and Department of Anatomy I, University of Cologne, Germany.
authors.forename: Marie-Louise
authors.initials: ML
authors.lastname: Koepke
authors.forename: Manfred
authors.initials: M
authors.lastname: Weber
authors.forename: Eckhard
authors.initials: E
authors.lastname: Schulze-Lohoff
authors.forename: Bogdan
authors.initials: B
authors.lastname: Beirowski
authors.forename: Stephan
authors.initials: S
authors.lastname: Segerer
authors.forename: Oliver
authors.initials: O
authors.lastname: Gross
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000235:genetics / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D024141:Collagen Type IV / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005109:Extracellular Matrix / Q000378:metabolism; D005355:Fibrosis / Q000209:etiology / Q000517:prevention & control; D005786:Gene Expression Regulation; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D009394:Nephritis, Hereditary / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011507:Proteinuria / Q000517:prevention & control; D011725:Pyridines / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014511:Uremia / Q000517:prevention & control
chemical_list: D001324:Autoantigens; D024141:Collagen Type IV; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011725:Pyridines; D053773:Transforming Growth Factor beta1; C057112:type IV collagen alpha3 chain; D002784:Cholesterol; C086276:cerivastatin