The Immunosuppressive Drug Mizoribine Directly Prevents Podocyte Injury in Puromycin Aminonucleoside Nephrosis

摘要

Background/Aims: Mizoribine (MZR) is an imidazole nuc-leoside 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.Wethods: Rats were intravenously injected once on day 0 with 100mg/kgof 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 |xg/ml of MZR and then treated with 30 |xg/ml of PAN. Results: In rat PAN nephrosis, treatment with MZR from days 0 to 14 almost completely inhibited proteinuria. Immunofluo-rescence 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'-monophos-phate dehydrogenase that is a known target enzyme of MZR as an immunosuppressant. MZR reduced PAN-induced inte-grin-linked kinase activation (ILK) and phosphorylation of glycogen synthase kinase-3beta (GSK3beta) in vivo and in vitro. Conclusion: MZR directly prevents PAN-induced podocyte injury, possibly by affecting signaling cascades involving ILKand GSK3P.