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NDT Advance Access originally published online on May 19, 2005
Nephrology Dialysis Transplantation 2005 20(8):1573-1581; doi:10.1093/ndt/gfh888
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© The Author [2005]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org

Original Article

Mizoribine reduces renal injury and macrophage infiltration in non-insulin-dependent diabetic rats

Yuichi Kikuchi, Toshihiko Imakiire, Muneharu Yamada, Takamitsu Saigusa, Toshitake Hyodo, Naomi Hyodo, Shigenobu Suzuki and Soichiro Miura

Second Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513 Japan

Correspondence and offprint requests to: Yuichi Kikuchi, MD, Second Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513 Japan. Email: grd1615{at}ndmc.ac.jp

Background. Macrophage infiltration in kidney is one of the most important events for the progression of diabetic nephropathy. Mycophenolate mofetil (MMF), an anti-inflammatory agent, has been shown to suppress macrophage infiltration and to improve renal injury in streptozotocin-induced diabetic kidneys. We examined whether mizoribine, which acts through immunosuppressive mechanisms similar to MMF, inhibits progression of diabetic nephropathy in non-insulin-dependent diabetic rats.

Methods. Male Otsuka Long–Evans Tokushima Fatty (OLETF) rats, a non-insulin-dependent diabetic model, and Long–Evans Tokushima Otsuka (LETO) rats, a non-diabetic control, were studied at 35 weeks of age. OLETF rats were randomized to receive mizoribine (5 or 10 mg/kg) or normal saline for 8 weeks. Histological changes such as glomerulosclerosis and interstitial fibrosis and the number of ED1- and CD5-positive cells in the kidney were assessed. By using reverse transcription–polymerase chain reaction (RT–PCR) and immunohistochemistry, monocyte chemoattractant protein-1 (MCP-1), osteopontin (OPN) and transforming growth factor (TGF)-ß1 expression in the kidney was also analysed.

Results. Urinary albumin excretion in OLETF rats increased compared with that in LETO rats. Administration of mizoribine suppressed urinary albumin excretion. Development of glomerulosclerosis, interstitial fibrosis and macrophage infiltration in the kidney was also inhibited by treatment with mizoribine. The expression of MCP-1, OPN and TGF-ß1 mRNA in untreated OLETF rats was significantly increased compared with that in LETO rats. By immunohistochemistry, increased expression of MCP-1, OPN and TGF-ß1 was found in the tubules and glomeruli of untreated OLETF rats. This expression was significantly suppressed by treatment with mizoribine.

Conclusions. Mizoribine inhibited renal macrophage accumulation and prevented the progression of glomerulosclerosis and interstitial fibrosis in non-insulin-dependent diabetic kidneys. In addition to standard treatments, anti-inflammatory agents may be useful for management of non-insulin-dependent diabetic nephropathy.

Keywords: anti-inflammatory agent; diabetic nephropathy; monocyte chemotactic protein-1; osteopontin; transforming growth factor-ß1


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