title: Fluvastatin prevents podocyte injury in a murine model of HIV-associated nephropathy.
abstract: BACKGROUND
  Recent studies have reported that statins have renoprotective effects, independent from lowering plasma cholesterol. In this study, we examined whether statins were beneficial in a murine model of HIV-associated nephropathy (HIVAN).
  
  
  METHODS
  We used conditional transgenic mice that express one of the HIV-1 accessory genes, vpr, selectively in podocytes using podocin promoter and the Tet-on system. These mice develop aggressive collapsing focal segmental glomerular sclerosis with massive proteinuria and deterioration of renal function within 4 weeks following heminephrectomy and doxycycline administration. Fluvastatin was administrated simultaneously with doxycycline, and the effect was compared with untreated controls after 4 weeks.
  
  
  RESULTS
  Fluvastatin at 10 mg/kg/day significantly decreased urinary albumin excretion (87 versus 11 mg/day, P < 0.01) and glomerular sclerosis (2.4 versus 1.0, P < 0.01, assessed by semi-quantitative scoring: 0-4). Fluvastatin also decreased serum creatinine and total cholesterol, but these differences were not statistically significant (0.36 versus 0.32 mg/dl, P = 0.35; 492 versus 378 mg/dl, P = 0.11, respectively). Phenotypic changes in podocytes, as indicated by the downregulation of nephrin, Wilms' tumour 1 and synaptopodin, along with upregulation of proliferating cell nuclear antigen, were attenuated by fluvastatin, suggesting its protective effects against podocyte injuries. In cultured podocytes, angiotensin II treatment decreased nephrin expression to 13% of basal levels, which was reversed to 58% by adding fluvastatin.
  
  
  CONCLUSIONS
  In conclusion, fluvastatin was effective in treating experimental HIVAN. The beneficial effect of this drug might be caused, in part, by preserving nephrin expression in podocytes against angiotensin II-mediated injury.
authors.affiliation: Department of Medicine and Clinical Science, Gunma University Graduate School of Medicine, Gunma, Japan.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Sakurai
authors.forename: Takashi
authors.initials: T
authors.lastname: Kuroiwa
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Ikeuchi
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Hiramatsu
authors.forename: Shigeru
authors.initials: S
authors.lastname: Takeuchi
authors.forename: Mai
authors.initials: M
authors.lastname: Tomioka
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Shigehara
authors.forename: Akito
authors.initials: A
authors.lastname: Maeshima
authors.forename: Yoriaki
authors.initials: Y
authors.lastname: Kaneko
authors.forename: Keiju
authors.initials: K
authors.lastname: Hiromura
authors.forename: Jeffery B
authors.initials: JB
authors.lastname: Kopp
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Nojima
mesh_terms: D016263:AIDS-Associated Nephropathy / Q000473:pathology / Q000517:prevention & control*; D000804:Angiotensin II / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use*; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005229:Fatty Acids, Monounsaturated / Q000627:therapeutic use*; D005455:Fluorescent Antibody Technique; D000077340:Fluvastatin; D016162:Genes, Wilms Tumor; D005923:Glomerulosclerosis, Focal Segmental / Q000517:prevention & control*; D007124:Immunoenzyme Techniques; D007211:Indoles / Q000627:therapeutic use*; D007668:Kidney / Q000166:cytology / Q000378:metabolism / Q000601:surgery; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000378:metabolism; D009392:Nephrectomy; D010641:Phenotype; D050199:Podocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011507:Proteinuria / Q000517:prevention & control*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D005229:Fatty Acids, Monounsaturated; D007211:Indoles; D008565:Membrane Proteins; D008840:Microfilament Proteins; C503968:Synpo protein, mouse; C113267:nephrin; D000804:Angiotensin II; D000077340:Fluvastatin