title: Rosuvastatin attenuates inflammation, apoptosis and fibrosis in a rat model of cyclosporine-induced nephropathy.
abstract: OBJECTIVE
  Cyclosporine (CsA)-induced kidney injury is characterized by renal dysfunction with inflammatory cell infiltrations, apoptosis and fibrosis. Pleiotropic effects of statins may exert anti-inflammatory, antiapoptotic and antifibrotic actions beyond lipid control. The aim of this study is to investigate whether rosuvastatin (RUS) has anti-inflammatory, antiapoptotic and antifibrotic effects on chronic CsA-induced nephropathy in a rat model.
  
  
  METHODS
  Male Sprague-Dawley rats fed a low-sodium diet were divided into three treatment groups: control (0.9% saline injection), CsA (15 mg/kg/day by subcutaneous injection), CsA + RUS (10 mg/kg/day by gastric gavage). Renal function, CsA level and lipid levels were measured at the end of 4 weeks. The expression of ED-1, transforming growth factor-β(1) (TGF-β(1)) and α-smooth muscle actin (α-SMA) for inflammation and fibrosis were examined by Western blot analysis. The expression levels of apoptosis-associated factors were examined by Western blot analysis. Apoptosis was evaluated using the terminal deoxynucleotidyl transferase-mediated biotin nick end-labeling (TUNEL) method.
  
  
  RESULTS
  Kidney function was decreased in CsA-treated rats compared with controls, which was attenuated by RUS. RUS did not affect the lipid level or the blood CsA level. TUNEL staining showed that RUS inhibited CsA-induced tubular apoptosis. RUS decreased CsA-induced increased expression of Bax/Bcl-2 ratio. The expressions of ED-1, α-SMA, TGF-β(1), Smad2/3, Smad4 and p-JNK were increased in CsA-treated rats, which were attenuated by RUS. Tubular atrophy and interstitial fibrosis in CsA-treated rats were attenuated by RUS supplementation.
  
  
  CONCLUSIONS
  RUS supplementation attenuates proinflammatory and apoptosis-related factors and inhibits the fibrotic pathways including the smad-dependent and smad-independent pathways in a rat model of CsA-induced nephropathy.
authors.affiliation: Department of Internal Medicine, Busan Medical Center, Busan, Republic of Korea.
authors.forename: Hyun Kyung
authors.initials: HK
authors.lastname: Nam
authors.forename: Seong Joo
authors.initials: SJ
authors.lastname: Lee
authors.forename: Moo Hyun
authors.initials: MH
authors.lastname: Kim
authors.forename: Jee Hyun
authors.initials: JH
authors.lastname: Rho
authors.forename: Young Ki
authors.initials: YK
authors.lastname: Son
authors.forename: Su Mi
authors.initials: SM
authors.lastname: Lee
authors.forename: Seong Eun
authors.initials: SE
authors.lastname: Kim
authors.forename: Ki Hyun
authors.initials: KH
authors.lastname: Kim
authors.forename: Won Suk
authors.initials: WS
authors.lastname: An
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015820:Cadherins / Q000378:metabolism; D016572:Cyclosporine / Q000009:adverse effects*; D004353:Drug Evaluation, Preclinical; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005464:Fluorobenzenes / Q000494:pharmacology / Q000627:therapeutic use*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000068718:Rosuvastatin Calcium; D051785:Smad Proteins / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D000199:Actins; D015820:Cadherins; D016572:Cyclosporine; D048049:Extracellular Signal-Regulated MAP Kinases; D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007166:Immunosuppressive Agents; D048031:JNK Mitogen-Activated Protein Kinases; D052247:Nitric Oxide Synthase Type II; D011506:Proteins; D011743:Pyrimidines; D000068718:Rosuvastatin Calcium; D051785:Smad Proteins; D013449:Sulfonamides; D053773:Transforming Growth Factor beta1; C508962:Tgfb1 protein, rat; C498862:Acta2 protein, rat; C496318:Nos2 protein, rat