title: Synergistic protective effects of mizoribine and angiotensin II receptor blockade on cyclosporine A nephropathy in rats.
abstract: BACKGROUND
  Chronic cyclosporine A (CsA) nephrotoxicity is manifested by renal dysfunction, progressive histopathological kidney lesions characterized by afferent arteriolopathy, and tubulointerstitial fibrosis. In addition to the direct toxic effect of CsA, many other etiological factors such as angiotensin II, transforming growth factor (TGF)-β, and macrophage infiltration are involved in this pathogenesis. This study investigated the hypothesis that concomitant administration of mizoribine (MZR) and angiotensin II receptor blockade (ARB) may prevent CsA nephrotoxicity in rats.
  
  
  METHODS
  Sprague-Dawley male rats were divided into the following seven groups: group 1, treated with CsA; group 2, treated with CsA + MZR; group 3, treated with CsA + valsartan (Val); group 4, treated with CsA + MZR + Val; group 5, treated with MZR; group 6, treated with Val; and group 7, controls (n = 5 each). Renal histopathology and the effect of CsA-induced nephrotoxicity on inflammatory mediators were evaluated.
  
  
  RESULTS
  Results of this study demonstrated that ARB administration significantly decreased arteriolopathy and that in comparison with monotherapy, concomitant administration of MZR and ARB further decreased arteriolopathy, fibrosis, macrophage infiltration, and TGF-β1 mRNA expression associated with CsA nephrotoxicity.
  
  
  CONCLUSIONS
  These findings indicate that MZR and ARB combination treatment provides synergistic protective effects against chronic CsA nephrotoxicity.
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Amane
authors.initials: A
authors.lastname: Endo
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Tomonosuke
authors.initials: T
authors.lastname: Someya
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Mayu
authors.initials: M
authors.lastname: Nakagawa
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Yayoi
authors.initials: Y
authors.lastname: Murano
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Sakuraya
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Hara
authors.affiliation: Division of Nephrology, Saitama Children's Medical Center, Saitama, Japan.
authors.forename: Shuichiro
authors.initials: S
authors.lastname: Fujinaga
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Ohtomo
authors.affiliation: Division of Pathology, Saitama Children's Medical Center, Saitama, Japan.
authors.forename: Hitohiko
authors.initials: H
authors.lastname: Murakami
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Shimizu
mesh_terms: D057911:Angiotensin Receptor Antagonists / Q000494:pharmacology*; D000818:Animals; D001835:Body Weight; D016572:Cyclosporine / Q000009:adverse effects*; D004357:Drug Synergism; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D007674:Kidney Diseases / Q000139:chemically induced / Q000517:prevention & control*; D008297:Male; D016133:Polymerase Chain Reaction; D051381:Rats; D017207:Rats, Sprague-Dawley; D012263:Ribonucleosides / Q000494:pharmacology*
chemical_list: D057911:Angiotensin Receptor Antagonists; D007166:Immunosuppressive Agents; D012263:Ribonucleosides; C010052:mizoribine; D016572:Cyclosporine