title: Rosuvastatin protects against angiotensin II-induced renal injury in a dose-dependent fashion.
abstract: OBJECTIVE
  We showed earlier that statin treatment ameliorates target-organ injury in a transgenic model of angiotensin (Ang) II-induced hypertension. We now test the hypothesis that rosuvastatin (1, 10, and 50 mg/kg/day) influences leukocyte adhesion and infiltration, prevents induction of inducible nitric oxide synthase (iNOS), and ameliorates target-organ damage in a dose-dependent fashion.
  
  
  METHODS
  We treated rats harboring the human renin and human angiotensinogen genes (dTGR) from week 4 to 8 (n = 20 per group). Untreated dTGR developed severe hypertension, cardiac hypertrophy, and renal damage, with a 100-fold increased albuminuria and focal cortical necrosis. Mortality of untreated dTGR at age 8 weeks was 59%.
  
  
  RESULTS
  Rosuvastatin treatment decreased mortality dose-dependently. Blood pressure was not affected. Albuminuria was reduced dose-dependently. Interstitial adhesion molecule (ICAM)-1 expression was markedly reduced by rosuvastatin, as were neutrophil and monocyte infiltration. Immunohistochemistry showed an increased endothelial and medial iNOS expression in small vessels, infiltrating cells, afferent arterioles, and glomeruli of dTGR. Immunoreactivity was stronger in cortex than medulla. Rosuvastatin markedly reduced the iNOS expression in both cortex and medulla. Finally, matrix protein (type IV collagen, fibronectin) expression was also dose- dependently reduced by rosuvastatin.
  
  
  CONCLUSIONS
  Our findings indicate that rosuvastatin dose- dependently ameliorates angiotensin II-induced-organ damage and almost completely prevents inflammation at the highest dose. The data implicate 3-hydroxy-3-methylglutaryl coenzyme A function in signaling events leading to target-organ damage.
authors.affiliation: Department of Nephrology, Medical School Hannover, Germany.
authors.forename: Joon-Keun
authors.initials: JK
authors.lastname: Park
authors.forename: Eero Ma
authors.initials: EM
authors.lastname: Mervaala
authors.forename: Dominik N
authors.initials: DN
authors.lastname: Muller
authors.forename: Jan
authors.initials: J
authors.lastname: Menne
authors.forename: Anette
authors.initials: A
authors.lastname: Fiebeler
authors.forename: Friedrich C
authors.initials: FC
authors.lastname: Luft
authors.forename: Hermann
authors.initials: H
authors.lastname: Haller
mesh_terms: D000419:Albuminuria / Q000139:chemically induced / Q000188:drug therapy; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D024141:Collagen Type IV / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005353:Fibronectins / Q000378:metabolism; D019084:Fluorescent Antibody Technique, Indirect; D005464:Fluorobenzenes / Q000494:pharmacology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D006973:Hypertension / Q000139:chemically induced / Q000401:mortality*; D007150:Immunohistochemistry; D007249:Inflammation / Q000139:chemically induced / Q000517:prevention & control*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007668:Kidney / Q000293:injuries* / Q000473:pathology; D007672:Kidney Cortex / Q000201:enzymology / Q000378:metabolism; D007679:Kidney Medulla / Q000201:enzymology / Q000378:metabolism; D008297:Male; D009000:Monocytes / Q000187:drug effects; D009336:Necrosis / Q000401:mortality / Q000473:pathology; D020556:Neutrophil Infiltration / Q000187:drug effects; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D024141:Collagen Type IV; D005353:Fibronectins; D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; D000804:Angiotensin II; D018799:Intercellular Adhesion Molecule-1; D000068718:Rosuvastatin Calcium; D052247:Nitric Oxide Synthase Type II