Protective effects of Mizoribine on Cyclosporine A nephropathy in rats.
The therapeutic benefits of Cyclosporine A (CsA) are often limited by the chronic nephrotoxicity of its long-term use. Chronic nephrotoxicity is manifested by renal function impairment and progressive histopathological kidney lesions characterized by tubular vacuolization, tubular necrosis, interstitial fibrosis, and afferent arteriolopathy. This study tested the hypothesis that the concurrent administration of Mizoribine (MZR) may improve chronic CsA nephrotoxicity. Sprague-Dawley male rats were divided into the following four groups: group 1, control (n = 6); group 2, treated with CsA alone (n = 5); group 3, treated with CsA and MZR (n = 4); and group 4, treated with MZR alone (n = 6). The anti-inflammatory and antifibrotic effects of MZR were studied by evaluating the concentrations of the inflammatory mediator, osteopontin, renal function, and histopathology. The interstitial fibrosis was stained blue with Elastica-Massontrichrome and the sections were quantified. The CsA-treated rats showed decreased renal function and increased histologic parameters in comparison with the control rats and also showed significantly increased interstitial fibrosis area and macrophage in comparison with the control rats. The CsA MZR treatment significantly improved the interstitial fibrosis area and macrophage in comparison with the CsA-treated rats. On the basis of these findings, we suggest MZR effectively attenuates renal macrophage accumulation and the progression of interstitial fibrosis.
Hara
Satoshi
S
Department of Pediatrics, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan. satoshi-h@y6.dion.ne.jp
Umino
Daisuke
D
Someya
Tomonosuke
T
Fujinaga
Shuichiro
S
Ohtomo
Yoshiyuki
Y
Murakami
Hitohiko
H
Shimizu
Toshiaki
T
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001835:Body Weight; D016572:Cyclosporine / Q000633:toxicity*; D018450:Disease Progression; D005355:Fibrosis; D007150:Immunohistochemistry / Q000379:methods; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007249:Inflammation; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D007674:Kidney Diseases / Q000188:drug therapy*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012263:Ribonucleosides / Q000494:pharmacology*
D000893:Anti-Inflammatory Agents; D007166:Immunosuppressive Agents; D012263:Ribonucleosides; C010052:mizoribine; D016572:Cyclosporine