title: Cerivastatin prevents angiotensin II-induced renal injury independent of blood pressure- and cholesterol-lowering effects.
abstract: BACKGROUND
  Statins are effective in prevention of end-organ damage; however, the benefits cannot be fully explained on the basis of cholesterol reduction. We used an angiotensin II (Ang II)-dependent model to test the hypothesis that cerivastatin prevents leukocyte adhesion and infiltration, induction of inducible nitric oxide synthase (iNOS), and ameliorates end-organ damage.
  
  
  METHODS
  We analyzed intracellular targets, such as mitogen-activated protein kinase and transcription factor (nuclear factor-kappaB and activator protein-1) activation. We used immunohistochemistry, immunocytochemistry, electrophoretic mobility shift assays, and enzyme-linked immunosorbent assay techniques. We treated rats transgenic for human renin and angiotensinogen (dTGR) chronically from week 4 to 7 with cerivastatin (0.5 mg/kg by gavage).
  
  
  RESULTS
  Untreated dTGR developed hypertension, cardiac hypertrophy, and renal damage, with a 100-fold increased albuminuria and focal cortical necrosis. dTGR mortality at the age of seven weeks was 45%. Immunohistochemistry showed increased iNOS expression in the endothelium and media of small vessels, infiltrating cells, afferent arterioles, and glomeruli of dTGR, which was greater in cortex than medulla. Phosphorylated extracellular signal regulated kinase (p-ERK) was increased in dTGR; nuclear factor-kappaB and activator protein-1 were both activated. Cerivastatin decreased systolic blood pressure compared with untreated dTGR (147 +/- 14 vs. 201 +/- 6 mm Hg, P < 0.001). Albuminuria was reduced by 60% (P = 0.001), and creatinine was lowered (0.45 +/- 0.01 vs. 0.68 +/- 0.05 mg/dL, P = 0. 003); however, cholesterol was not reduced. Intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 expression was diminished, while neutrophil and monocyte infiltration in the kidney was markedly reduced. ERK phosphorylation and transcription factor activation were reduced. In addition, in vitro incubation of vascular smooth muscle cells with cerivastatin (0.5 micromol/L) almost completely prevented the Ang II-induced ERK phosphorylation.
  
  
  CONCLUSIONS
  Cerivastatin reduced inflammation, cell proliferation, and iNOS induction, which led to a reduction in cellular damage. Our findings suggest that 3-hydroxy-3-methylglutaryl coenzyme (HMG-CoA) reductase inhibition ameliorates Ang II-induced end-organ damage. We suggest that these effects were independent of cholesterol.
authors.affiliation: Franz Volhard Clinic, Medical Faculty of the Charité, Humboldt University of Berlin, Berlin, Germany.
authors.forename: J K
authors.initials: JK
authors.lastname: Park
authors.forename: D N
authors.initials: DN
authors.lastname: Müller
authors.forename: E M
authors.initials: EM
authors.lastname: Mervaala
authors.forename: R
authors.initials: R
authors.lastname: Dechend
authors.forename: A
authors.initials: A
authors.lastname: Fiebeler
authors.forename: F
authors.initials: F
authors.lastname: Schmidt
authors.forename: M
authors.initials: M
authors.lastname: Bieringer
authors.forename: O
authors.initials: O
authors.lastname: Schäfer
authors.forename: C
authors.initials: C
authors.lastname: Lindschau
authors.forename: W
authors.initials: W
authors.lastname: Schneider
authors.forename: D
authors.initials: D
authors.lastname: Ganten
authors.forename: F C
authors.initials: FC
authors.lastname: Luft
authors.forename: H
authors.initials: H
authors.lastname: Haller
mesh_terms: D000419:Albuminuria / Q000139:chemically induced / Q000188:drug therapy / Q000201:enzymology; D000804:Angiotensin II / Q000494:pharmacology*; D000808:Angiotensinogen / Q000235:genetics; D000818:Animals; D030801:Animals, Genetically Modified; D001794:Blood Pressure / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D002784:Cholesterol / Q000097:blood*; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis; D007668:Kidney / Q000166:cytology / Q000187:drug effects; D007676:Kidney Failure, Chronic / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology; D007962:Leukocytes / Q000737:chemistry / Q000166:cytology; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009929:Organ Size / Q000187:drug effects; D010766:Phosphorylation; D010960:Plasminogen Activators / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000235:genetics; D013925:Thromboplastin / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014508:Urea / Q000097:blood; D019010:Vascular Cell Adhesion Molecule-1 / Q000032:analysis; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D016328:NF-kappa B; D011725:Pyridines; D018808:Transcription Factor AP-1; D019010:Vascular Cell Adhesion Molecule-1; D014662:Vasoconstrictor Agents; D000808:Angiotensinogen; D000804:Angiotensin II; D018799:Intercellular Adhesion Molecule-1; D014508:Urea; D013925:Thromboplastin; D002784:Cholesterol; C086276:cerivastatin; D003404:Creatinine; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D020928:Mitogen-Activated Protein Kinases; D010960:Plasminogen Activators; D012083:Renin