Mizoribine reduces renal injury and macrophage infiltration in non-insulin-dependent diabetic rats.
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)-beta1 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-beta1 mRNA in untreated OLETF rats was significantly increased compared with that in LETO rats. By immunohistochemistry, increased expression of MCP-1, OPN and TGF-beta1 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.
Kikuchi
Yuichi
Y
Second Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513 Japan. grd1615@ndmc.ac.jp
Imakiire
Toshihiko
T
Yamada
Muneharu
M
Saigusa
Takamitsu
T
Hyodo
Toshitake
T
Hyodo
Naomi
N
Suzuki
Shigenobu
S
Miura
Soichiro
S
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D005355:Fibrosis / Q000188:drug therapy* / Q000473:pathology; D005923:Glomerulosclerosis, Focal Segmental / Q000188:drug therapy* / Q000473:pathology; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors; D007124:Immunoenzyme Techniques; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009395:Nephritis, Interstitial / Q000188:drug therapy* / Q000473:pathology; D053495:Osteopontin; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D020334:Rats, Inbred OLETF; D020318:Rats, Long-Evans; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012263:Ribonucleosides / Q000627:therapeutic use*; D012795:Sialoglycoproteins / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1
D000894:Anti-Inflammatory Agents, Non-Steroidal; D018932:Chemokine CCL2; D012333:RNA, Messenger; D012263:Ribonucleosides; D012795:Sialoglycoproteins; C506897:Spp1 protein, rat; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D053495:Osteopontin; C010052:mizoribine; D007168:IMP Dehydrogenase