title: Carbamylated erythropoietin ameliorates cyclosporine nephropathy without stimulating erythropoiesis.
abstract: The introduction of cyclosporine (CsA) has improved graft survival, but it causes nephropathy, which limits its clinical utility. Recently, we reported that carbamylated erythropoietin (CEPO) protected kidneys from ischemia reperfusion injury as well as EPO. To investigate the clinical  applications of CEPO, we next evaluated the long-term therapeutic effect of CEPO using a CsA-induced nephropathy model. CsA caused renal dysfunction, while EPO/CEPO administration significantly improved renal function. EPO treatment significantly increased Hb concentration, while CEPO treatment  neither enhanced nor reduced Hb concentration. CsA treatment induced tubular apoptosis, while EPO/CEPO administration inhibited it and increased PI3 kinase activation and Akt phosphorylation. In parallel, morphological assessment revealed that EPO/CEPO significantly reduced CsA-induced interstitial  fibrosis and inhibited interstitial macrophage infiltration. In addition, real-time RT-PCR demonstrated that cortical mRNA levels of TGF-β1 and type I collagen were suppressed in the EPO/CEPO group. These results suggest a new therapeutic approach using CEPO to protect kidneys from CsA-induced  nephropathy.
authors.affiliation: Department of Specific Organ Regulation (Urology), Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Toyofumi
authors.initials: T
authors.lastname: Abe
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Isaka
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Imamura
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Kakuta
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Okumi
authors.forename: Koji
authors.initials: K
authors.lastname: Yazawa
authors.forename: Naotsugu
authors.initials: N
authors.lastname: Ichimaru
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Tsuda
authors.forename: Norio
authors.initials: N
authors.lastname: Nonomura
authors.forename: Shiro
authors.initials: S
authors.lastname: Takahara
authors.forename: Akihiko
authors.initials: A
authors.lastname: Okuyama
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D016572:Cyclosporine / Q000633:toxicity*; D004195:Disease Models, Animal; D004285:Dogs; D004920:Erythropoiesis; D004921:Erythropoietin / Q000031:analogs & derivatives* / Q000494:pharmacology; D005355:Fibrosis / Q000517:prevention & control; D006454:Hemoglobins / Q000032:analysis; D006801:Humans; D007166:Immunosuppressive Agents / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D007674:Kidney Diseases / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008264:Macrophages / Q000276:immunology; D008297:Male; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000517:prevention & control; D015398:Signal Transduction / Q000187:drug effects; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism
chemical_list: D024042:Collagen Type I; D006454:Hemoglobins; D007166:Immunosuppressive Agents; D053773:Transforming Growth Factor beta1; C488171:carbamylated erythropoietin; D004921:Erythropoietin; D016572:Cyclosporine; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt