title: A new recombinant MnSOD prevents the cyclosporine A-induced renal impairment.
abstract: BACKGROUND
  Cyclosporine A (CsA) is one of the most frequently used anticalcineurinic drugs for preventing graft rejection and autoimmune disease. Its use is hampered by nephrotoxic effects, namely an impairment of the glomerular filtration rate (GFR) and hypertension. Evidence suggests that reactive oxygen species (ROS) play a causal role in the nephrotoxicity. The present study aims to investigate in vivo the effects of a new recombinant mitochondrial manganese-containing superoxide dismutase (rMnSOD), a strong antioxidant, on the CsA-induced nephotoxicity.
  
  
  METHODS
  Rats were treated with CsA (25 mg/kg/day) alone or in combination with rMnSOD (10 µg/kg/day) for 7 days. At the end of the treatment, GFR was estimated by inulin clearance (mL/min/100 g b.w.) and the mean arterial pressure (MAP) was recorded through a catheter inserted in the carotid artery. Superoxide concentration within the cells of the abdominal aorta was quantified from the oxidation of dihydroethidium (DHE). In kidney tissues, ROS levels were measured by the 2'7' dichloroflurescin diacetate assay. Renal morphology was examined at the histochemistry level.
  
  
  RESULTS
  CsA-treated rats showed a severe decrease in GFR (0.34 ± 0.17 versus 0.94 ± 0.10 in control, P < 0.001) which was prevented by rMnSOD co-administration (0.77 ± 0.10). CsA-injected animals presented with higher blood pressure which was unaffected by rMnSOD. ROS levels both in the aorta and in renal tissue were significantly increased by CsA treatment, and normalized by the co-administration with rMnSOD. This effect was, partly, paralleled by the recovery from CsA-induced morphological lesions.
  
  
  CONCLUSIONS
  Administration of rMnSOD prevents CsA-mediated impairment of the GFR along with morphological alteration. This effect could be related to the inhibition of ROS.
authors.affiliation: Division of Nephrology, Department of Cardio-Thoracic and Respiratory Sciences, Second University of Naples, Naples, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Damiano
authors.forename: Francesco
authors.initials: F
authors.lastname: Trepiccione
authors.forename: Roberto
authors.initials: R
authors.lastname: Ciarcia
authors.forename: Roberto
authors.initials: R
authors.lastname: Scanni
authors.forename: Manuela
authors.initials: M
authors.lastname: Spagnuolo
authors.forename: Leonida
authors.initials: L
authors.lastname: Manco
authors.forename: Antonella
authors.initials: A
authors.lastname: Borrelli
authors.forename: Clemente
authors.initials: C
authors.lastname: Capasso
authors.forename: Roberto
authors.initials: R
authors.lastname: Mancini
authors.forename: Antonella
authors.initials: A
authors.lastname: Schiattarella
authors.forename: Anna
authors.initials: A
authors.lastname: Iervolino
authors.forename: Enza
authors.initials: E
authors.lastname: Zacchia
authors.forename: Andrea
authors.initials: A
authors.lastname: Bata-Csere
authors.forename: Salvatore
authors.initials: S
authors.lastname: Florio
authors.forename: Pietro
authors.initials: P
authors.lastname: Anastasio
authors.forename: Rosamaria
authors.initials: R
authors.lastname: Pollastro
authors.forename: Aldo
authors.initials: A
authors.lastname: Mancini
authors.forename: Giovambattista
authors.initials: G
authors.lastname: Capasso
mesh_terms: D000818:Animals; D016572:Cyclosporine / Q000494:pharmacology*; D005919:Glomerular Filtration Rate; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007677:Kidney Function Tests; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology*; D051437:Renal Insufficiency / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D013482:Superoxide Dismutase / Q000378:metabolism*
chemical_list: D007166:Immunosuppressive Agents; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D016572:Cyclosporine; D013482:Superoxide Dismutase
keywords: cyclosporine; nephrotoxicity; reactive oxygen species; superoxide dismutase