Evaluation of oxidative stress in d -serine induced nephrotoxicity

• Published in: Toxicology (Amsterdam) Vol. 229; no. 1; pp. 123 - 135
• Main Authors: Orozco-Ibarra, Marisol, Medina-Campos, Omar Noel, Sánchez-González, Dolores Javier, Martínez-Martínez, Claudia María, Floriano-Sánchez, Esaú, Santamaría, Abel, Ramirez, Victoria, Bobadilla, Norma A, Pedraza-Chaverri, José
• Format: Journal Article
• Language: English
• Published: Shannon Elsevier Ireland Ltd 05-01-2007; Amsterdam Elsevier Science
• Subjects: Acetylglucosaminidase - urine; Amitrole - pharmacology; Animals; Antioxidants - metabolism; Biological and medical sciences; Blotting, Western; Catalase - antagonists & inhibitors; Catalase - metabolism; Cell Adhesion Molecules - genetics; Cell Adhesion Molecules - metabolism; Creatinine - blood; d-Serine; Dose-Response Relationship, Drug; Emergency; Kidney Diseases - blood; Kidney Diseases - chemically induced; Kidney Diseases - urine; Lipid Peroxidation - drug effects; Male; Malondialdehyde - chemistry; Malondialdehyde - metabolism; Medical sciences; Membrane Proteins - genetics; Membrane Proteins - metabolism; Metalloporphyrins - pharmacology; Nephrotoxicity; Oxidative Stress; Rats; Rats, Sprague-Dawley; Reproducibility of Results; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; RNA, Messenger - metabolism; Serine - administration & dosage; Serine - chemistry; Serine - toxicity; Stereoisomerism; Tin Compounds - pharmacology; Toxicity Tests - methods; Toxicology; Oxidative stress; d-Serine; Nephrotoxicity; Kidney disease; Evaluation; Urinary system disease; Toxicity; Aminoacid; Serine; D-Serine
• ISSN: 0300-483X; 1879-3185
• DOI: 10.1016/j.tox.2006.10.008

Abstract It has been suggested that oxidative stress is involved in d -serine-induced nephrotoxicity. The purpose of this study was to assess if oxidative stress is involved in this experimental model using several approaches including (a) the determination of several markers of oxidative stress and the activity of some antioxidant enzymes in kidney and (b) the use of compounds with antioxidant or prooxidant effects. Rats were sacrificed at several periods of time (from 3 to 24 h) after a single i.p. injection of d -serine (400 mg/kg). Control rats were injected with l -serine (400 mg/kg) and sacrificed 24 h after. The following markers were used to assess the temporal aspects of renal damage: (a) urea nitrogen (BUN) and creatinine in blood serum, (b) kidney injury molecule (KIM-1) mRNA levels, and (c) tubular necrotic damage. In addition, creatinine clearance, proteinuria, and urinary excretion of N -acetyl-β- d -glucosaminidase (NAG) were measured 24 h after d -serine injection. Protein carbonyl content, malondialdehyde (MDA), 4-hydroxy-2-nonenal (4-HNE), fluorescent products of lipid peroxidation, reactive oxygen species (ROS), glutathione (GSH) content, and heme oxygenase-1 (HO-1) expression were measured as markers of oxidative stress in the kidney. Additional experiments were performed using the following compounds with antioxidant or pro-oxidant effects before d -serine injection: (a) α-phenyl- tert -butyl-nitrone (PBN), a spin trapping agent; (b) 5,10,15,20-tetrakis (4-sulfonatophenyl) porphyrinato iron(III) (FeTPPS), a soluble complex able to metabolize peroxynitrite; (c) aminotriazole (ATZ), a catalase (CAT) inhibitor; (d) stannous chloride (SnCl2 ), an HO-1 inductor; (e) tin mesoporphyrin (SnMP), an HO inhibitor. In the time-course study, serum creatinine and BUN increased significantly on 15–24 and 20–24 h, respectively, and KIM-1 mRNA levels increased significantly on 6–24 h. Histological analyses revealed tubular necrosis at 12 h. The activity of antioxidant enzymes catalase, superoxide dismutase, glutathione peroxidase, and glutathione reductase remained unchanged at all times studied. Protein carbonyl content, MDA, 4-HNE, and ROS remained unchanged at all time-points studied. GSH content decreased transiently on 9 and 12 h. Interestingly, fluorescent products of lipid peroxidation decreased significantly on 3–24 h. HO-1 expression was undetectable by Western blot and the immunohistochemistry studies revealed that the intensity of HO-1 staining was weak. The administration of PBN, FeTPPS, ATZ, SnCl2 , and SnMP did not prevent or enhance renal damage induced by d -serine. Our data taken as a whole suggest that oxidative stress is not involved in the early phase of the nephrotoxicity induced by d -serine.