title: Effects of cyclosporine in osteopontin null mice.
abstract: BACKGROUND
  Osteopontin (OPN) is a macrophage adhesive and cell survival factor that is up-regulated in tubules in tubulointerstitial disease. We have previously reported that rats with cyclosporine (CsA) nephropathy have increased tubular osteopontin that correlates with the infiltration of macrophages and interstitial fibrosis. This study tested the hypothesis that the absence of OPN would ameliorate CsA nephropathy.
  
  
  METHODS
  OPN knockout (-/-) and wild type (+/+) mice were fed a low salt diet (Na+ 0.01%) for one week and then received daily CsA injections (30 mg/kg, SC) until sacrifice at two weeks. Afferent arteriolopathy, tubulointerstitial injury, macrophage infiltration, collagen III deposition, transforming growth factor-beta (TGF-beta) expression, and tubular and interstitial cell proliferation and apoptosis were evaluated.
  
  
  RESULTS
  Wild type mice developed early features of CsA nephropathy, with arteriolar hyalinosis and cortical and tubulointerstitial fibrosis. Despite comparable CsA levels, OPN-/- mice had less arteriolopathy (15 vs. 24%, P < 0.05), a 20% reduction in cortical macrophage infiltration (P < 0.05), and 20% reduction in interstitial collagen deposition (P < 0.05). OPN-/- mice also showed less cortical interstitial cell proliferation but no differences in tubular cell proliferation or apoptosis. OPN+/+ mice also developed some neurotoxicity, consisting of ataxia, and this was associated with increased mortality at two weeks.
  
  
  CONCLUSIONS
  OPN partially mediates arteriolopathy, early macrophage recruitment and fibrosis in murine CsA nephropathy. OPN also may be involved in CsA associated neurotoxicity.
authors.affiliation: Division of Nephrology, Department of Pathology, University of Washington, Seattle, Washington, USA.
authors.forename: Marilda
authors.initials: M
authors.lastname: Mazzali
authors.forename: Jeremy
authors.initials: J
authors.lastname: Hughes
authors.forename: Marcio
authors.initials: M
authors.lastname: Dantas
authors.forename: Lucy
authors.initials: L
authors.lastname: Liaw
authors.forename: Susan
authors.initials: S
authors.lastname: Steitz
authors.forename: Charles E
authors.initials: CE
authors.lastname: Alpers
authors.forename: Raimund H
authors.initials: RH
authors.lastname: Pichler
authors.forename: Hui Y
authors.initials: HY
authors.lastname: Lan
authors.forename: Cecilia M
authors.initials: CM
authors.lastname: Giachelli
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Shankland
authors.forename: William G
authors.initials: WG
authors.lastname: Couser
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Johnson
mesh_terms: D000818:Animals; D017209:Apoptosis; D002455:Cell Division; D016572:Cyclosporine / Q000633:toxicity*; D005355:Fibrosis; D007166:Immunosuppressive Agents / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D008264:Macrophages / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D053495:Osteopontin; D012333:RNA, Messenger / Q000032:analysis; D012795:Sialoglycoproteins / Q000235:genetics / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000235:genetics; D053773:Transforming Growth Factor beta1
chemical_list: D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D012795:Sialoglycoproteins; C506896:Spp1 protein, mouse; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D053495:Osteopontin; D016572:Cyclosporine