title: The role of peroxisome-proliferator-activating receptor gamma agonists: rosiglitazone and 15-deoxy-delta12,14-prostaglandin J2 in chronic experimental cyclosporine A-induced nephrotoxicity.
abstract: Cyclosporine A(CsA) is an immunosuppressor frequently used in the transplant surgery and in the treatment of autoimmune diseases. The therapeutic benefits of CsA are often limited by it's main side effect-nephrotoxicity. Mechanisms of chronic CsA- induced renal damage include: activation of renin-angiotensin-aldosterone system, upregulation of transforming growth factor beta (TGF-β), oxidative stress. This study was undertaken to investigate the protective effect of the peroxisome-proliferator-activated receptors gamma (PPARs-γ) agonists: rosiglitazone and 15-deoxy-Δ12,14-prostaglandin J2 (PGDJ2), against CsA-induced kidney injury in male Wistar rats. CsA was administered subcutaneously at a dose of 15 mg/kg/day for 28 days. Both PPAR-γ agonists were given for 28 days 0.5 hour before the administration of CsA. Rosiglitazone was administered orally at a dose of 8 mg/kg/day and PGDJ2 was given intraperitoneally at a dose of 30 μg/kg/day. CsA induced renal failure was evidenced by increased serum levels of urea, uric acid and creatinine. Serum concentrations of GSH and GSSG, lipid peroxidation products as well as NAD+/NADH, NADP+/NADPH and ADP/ATP ratios showed, that CsA induced oxidative stress and evoked an imbalanced red-ox state in the kidney. Light and electron microscope studies showed degenerative changes within renal tubules with damage to their mitochondria, interstitial fibrosis and arteriolopathy. Immunohistochemical expression of profibrotic TGF-β was assessed. The biochemical and morphological changes induced by CsA were limited by administration of both rosiglitazone and PGDJ2. Ultrastructural examination of renal tubular epithelial cells showed marked improvement within mitochondria. Our results indicate that both PPAR-γ agonists used in the experiment may play an important role in protecting against CsA-induced damage in the kidney.
authors.affiliation: Department of Clinical Pathomorphology, Medical University, Lublin, Poland. agnieszka.korolczuk@wp.pl.
authors.forename: A
authors.initials: A
authors.lastname: Korolczuk
authors.forename: M
authors.initials: M
authors.lastname: Maciejewski
authors.forename: A
authors.initials: A
authors.lastname: Smolen
authors.forename: J
authors.initials: J
authors.lastname: Dudka
authors.forename: G
authors.initials: G
authors.lastname: Czechowska
authors.forename: I
authors.initials: I
authors.lastname: Widelska
mesh_terms: D000818:Animals; D003404:Creatinine / Q000097:blood; D016572:Cyclosporine; D004195:Disease Models, Animal; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009243:NAD / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D020011:Protective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017208:Rats, Wistar; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology / Q000627:therapeutic use*; D014508:Urea / Q000097:blood; D014527:Uric Acid / Q000097:blood
chemical_list: C097240:15-deoxy-delta(12,14)-prostaglandin J2; D047495:PPAR gamma; D020011:Protective Agents; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D009243:NAD; D014527:Uric Acid; D009249:NADP; D016572:Cyclosporine; D014508:Urea; D003404:Creatinine; D005978:Glutathione; D015230:Prostaglandin D2; D019803:Glutathione Disulfide