title: Pioglitazone ameliorates methotrexate-induced renal endothelial dysfunction via amending detrimental changes in some antioxidant parameters, systemic cytokines and Fas production.
abstract: Methotrexate (MTX) is widely used in treatment of cancers and autoimmune diseases. However, nephrotoxicity is one of its most important side effects. The peroxisome proliferator-activated receptor gamma agonist, pioglitazone, is known to exert antiinflammatory and reno-protective effects in various kidney injuries. The purpose of this study was to investigate the potential involvement of endothelial damage in MTX-induced renal injury and to elaborate the possible protective effect of pioglitazone against MTX-induced endothelial impairment. Compared with saline-treated rats, treatment with MTX (7mg/kg for 3days) caused significant elevations in serum levels of urea and creatinine, increased renal nitrate/nitrite level and impaired renovascular responsiveness of isolated perfused kidney to endothelium-dependent vasodilations induced by acetylcholine (0.01-2.43nmol) and isoprenaline (1μmol). These effects were abolished by concurrent treatment with pioglitazone (2.5mg/kg, for 5days starting 2days before MTX). Alternatively, MTX treatment did not affect endothelium-independent renovascular relaxation induced by sodium nitroprusside (0.001-10μmole). The possibility that alterations in renal antioxidants, circulating cytokine and apoptotic factor (Fas) levels contributed to MTX-pioglitazone interaction was assessed. Pioglitazone treatment abrogated renal oxidative stress (decreased reduced glutathione and catalase activity and increased malondialdehyde), elevated serum cytokine (interleukin-6, interleukin-10, tumor necrosis factor-alpha and transforming growth factor-beta1) and Fas induced by MTX. Histologically, MTX caused defused tubular cells swelling and vacuolization associated with endothelial damage in renal arterioles. These effects disappeared upon co-treated with pioglitazone. Collectively, pioglitazone abolished MTX-induced endothelium dysfunction and nephrotoxicity via ameliorating oxidative stress and rectifying cytokines and Fas abnormalities caused by MTX.
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt.
authors.forename: Sahar M
authors.initials: SM
authors.lastname: El-Gowilly
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt. Electronic address: meeshoo7@hotmail.com.
authors.forename: Mai M
authors.initials: MM
authors.lastname: Helmy
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt.
authors.forename: Hanan M
authors.initials: HM
authors.lastname: El-Gowelli
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D007674:Kidney Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D008727:Methotrexate / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D000077205:Pioglitazone; D051381:Rats; D017208:Rats, Wistar; D045162:Thiazolidinediones / Q000494:pharmacology*; D019014:fas Receptor / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D016207:Cytokines; D045162:Thiazolidinediones; D019014:fas Receptor; D008315:Malondialdehyde; D005978:Glutathione; D000077205:Pioglitazone; D008727:Methotrexate
keywords: Endothelium; Kidney; Methotrexate; Pioglitazone