title: The immunosuppressive drug mizoribine directly prevents podocyte injury in puromycin aminonucleoside nephrosis.
abstract: OBJECTIVE
  Mizoribine (MZR) is an imidazole nucleoside used as a therapeutic immunosuppressive agent. Though a previous report showed that MZR ameliorates proteinuria in puromycin aminonucleoside (PAN) nephropathy, the effect of MZR on podocytes has not been clarified. In this study, we determined whether MZR directly prevents PAN-induced podocyte injury.
  
  
  METHODS
  Rats were intravenously injected once on day 0 with 100 mg/kg of PAN and received daily subcutaneous injections of MZR at a dose of 10 mg/kg from days 0 to 14. Cultured podocytes were pretreated with 50 microg/ml of MZR and then treated with 30 microg/ml of PAN.
  
  
  RESULTS
  In rat PAN nephrosis, treatment with MZR from days 0 to 14 almost completely inhibited proteinuria. Immunofluorescence staining of nephrin was diminished, showing a discontinuous pattern in saline-treated PAN rats. In contrast, MZR treatment resulted in maintenance of a normal linear pattern. In cultured podocytes exposed to PAN, the percentages of viable cells were significantly increased with MZR treatment. The protective effect of MZR on PAN-induced podocyte injury was independent of inosine 5'-monophosphate dehydrogenase that is a known target enzyme of MZR as an immunosuppressant. MZR reduced PAN-induced integrin-linked kinase activation (ILK) and phosphorylation of glycogen synthase kinase-3beta (GSK3beta) in vivo and in vitro.
  
  
  CONCLUSIONS
  MZR directly prevents PAN-induced podocyte injury, possibly by affecting signaling cascades involving ILK and GSK3beta.
authors.affiliation: Department of Medicine and Clinical Science, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Takeuchi
authors.forename: Keiju
authors.initials: K
authors.lastname: Hiromura
authors.forename: Mai
authors.initials: M
authors.lastname: Tomioka
authors.forename: Satoshi
authors.initials: S
authors.lastname: Takahashi
authors.forename: Toru
authors.initials: T
authors.lastname: Sakairi
authors.forename: Akito
authors.initials: A
authors.lastname: Maeshima
authors.forename: Yoriaki
authors.initials: Y
authors.lastname: Kaneko
authors.forename: Takashi
authors.initials: T
authors.lastname: Kuroiwa
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Nojima
mesh_terms: D000818:Animals; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis; D009401:Nephrosis / Q000139:chemically induced / Q000188:drug therapy*; D050199:Podocytes / Q000187:drug effects*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011692:Puromycin Aminonucleoside / Q000037:antagonists & inhibitors; D051381:Rats; D017208:Rats, Wistar; D012263:Ribonucleosides / Q000627:therapeutic use*; D000099200:Scaffold Protein ILK
chemical_list: D007168:IMP Dehydrogenase; D007166:Immunosuppressive Agents; D008565:Membrane Proteins; D017346:Protein Serine-Threonine Kinases; D011692:Puromycin Aminonucleoside; D012263:Ribonucleosides; D000099200:Scaffold Protein ILK; C113267:nephrin; C010052:mizoribine