title: HMG-CoA reductase inhibitor ameliorates diabetic nephropathy by its pleiotropic effects in rats.
abstract: BACKGROUND
  An inflammatory process may be one of the critical factors that contribute to the development of diabetic nephropathy (DN). We reported previously that intercellular adhesion molecule-1 (ICAM-1) is up-regulated and promotes macrophage infiltration in the glomeruli of diabetic rats. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have recently been emphasized to have anti-inflammatory effects; inhibition of leukocyte adhesion and migration, independent of the cholesterol-lowering effect. The present study was designed to test the hypothesis that statins prevent the development of DN by pleiotropic effects.
  
  
  METHODS
  Streptozotocin-induced diabetic rats were treated with cerivastatin (0.5 mg/kg body weight) or vehicle for 4 weeks. We analysed glomerular macrophage infiltration and ICAM-1 expression. We also evaluated major regulators of ICAM-1, activation of nuclear factor-kappa B (NF-kappaB) using electrophoretic mobility shift assay, and oxidative stress.
  
  
  RESULTS
  Statin treatment reduced urinary albumin excretion (UAE) (2.96+/-0.18 vs 2.38+/-0.06; log(10) UAE, P<0.05), glomerular size (12 150+/-329 vs 9963+/-307 micro m(2), P<0.05), and lowered blood pressure, compared with untreated diabetic rats. Immunohistochemistry revealed that macrophage infiltration and ICAM-1 expression in glomeruli were increased in diabetic rats and were inhibited by statin treatment. Renal NF-kappaB activity, urinary excretion and renal deposition of 8-OHdG were increased in diabetic rats, and reduced by statin treatment.
  
  
  CONCLUSIONS
  Statin treatment prevented glomerular injury, independent of the cholesterol-lowering effects. Our findings suggest that the beneficial effect might be mediated by pleiotropic effects including an anti-inflammatory action through a reduction of oxidative stress, NF-kappaB activation, ICAM-1 expression and macrophage infiltration in the early phase of DN.
authors.affiliation: Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, Okayama 700-8558, Japan.
authors.forename: Hitomi
authors.initials: H
authors.lastname: Usui
authors.forename: Kenichi
authors.initials: K
authors.lastname: Shikata
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Matsuda
authors.forename: Shinichi
authors.initials: S
authors.lastname: Okada
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ogawa
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Yamashita
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Hida
authors.forename: Minoru
authors.initials: M
authors.lastname: Satoh
authors.forename: Jun
authors.initials: J
authors.lastname: Wada
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Makino
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000652:urine; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D003928:Diabetic Nephropathies / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000502:physiology; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
chemical_list: D000893:Anti-Inflammatory Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D016328:NF-kappa B; D011725:Pyridines; D018799:Intercellular Adhesion Molecule-1; D000080242:8-Hydroxy-2'-Deoxyguanosine; C086276:cerivastatin; D003849:Deoxyguanosine