title: Methotrexate prevents renal injury in experimental diabetic rats via anti-inflammatory actions.
abstract: Recent studies suggested the involvement of inflammatory processes in the pathogenesis of diabetic nephropathy. Methotrexate (MTX), a folic acid antagonist, is widely used for the treatment of inflammatory diseases. Recently, it has been shown that treatment with low-dose MTX reduces the cardiovascular mortality in patients with rheumatoid arthritis, suggesting that MTX has anti-atherosclerotic effects via its anti-inflammatory actions. This study was designed to determine the anti-inflammatory effects of this agent on diabetic nephropathy. Diabetes was induced in Sprague-Dawley rats with streptozotocin, and MTX (0.5 or 1.0 mg/kg) was administered once a week for 8 wk. Treatment with MTX reduced urinary albumin excretion, mesangial matrix expansion, macrophage infiltration, expression of TGF-beta and type IV collagen, and intercellular adhesion molecule-1 in glomeruli. MTX also reduced the high glucose-induced NF-kappaB activation in vitro and in vivo. The results indicate that intermittent administration of MTX prevented renal injuries without changes in blood glucose level and BP in experimental diabetic rats. The protective effects of MTX are suggested to be mediated by its anti-inflammatory actions through inhibition of NF-kappaB activation and consequent reduction of intercellular adhesion molecule-1 expression and macrophage infiltration. The results suggest that anti-inflammatory agents might be beneficial for the treatment of diabetic nephropathy.
authors.affiliation: Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama, Japan 700-8558.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Yozai
authors.forename: Kenichi
authors.initials: K
authors.lastname: Shikata
authors.forename: Motofumi
authors.initials: M
authors.lastname: Sasaki
authors.forename: Atsuhiro
authors.initials: A
authors.lastname: Tone
authors.forename: Sakiko
authors.initials: S
authors.lastname: Ohga
authors.forename: Hitomi
authors.initials: H
authors.lastname: Usui
authors.forename: Shinichi
authors.initials: S
authors.lastname: Okada
authors.forename: Jun
authors.initials: J
authors.lastname: Wada
authors.forename: Ryo
authors.initials: R
authors.lastname: Nagase
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ogawa
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Shikata
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Makino
mesh_terms: D000419:Albuminuria / Q000517:prevention & control; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D003928:Diabetic Nephropathies / Q000517:prevention & control*; D008297:Male; D008727:Methotrexate / Q000627:therapeutic use*; D016328:NF-kappa B / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000893:Anti-Inflammatory Agents; D016328:NF-kappa B; D008727:Methotrexate