title: Role of peroxynitrite in sepsis-induced acute kidney injury in an experimental model of sepsis in rats.
abstract: The mechanisms involved in sepsis-induced acute kidney injury (AKI) are unknown. We investigated the role of nitrosative stress in sepsis-induced AKI by studying the effects of manganese (III) tetrakis-(1-methyl-4-pyridyl) porphyrin pentachloride (MnTMPyP), a peroxynitrite decomposition catalyst, and aminoguanidine (AG), a selective nitric oxide synthase 2 (NOS2) inhibitor and peroxynitrite scavenger, on kidney function of rats subjected to cecal ligation and puncture (CLP). Sprague-Dawley rats (weighing 350 [SD, 50] g) were treated with MnTMPyP (6 mg/kg i.p.) or AG (50 mg/kg i.p.) at t = 12 and 24 h after CLP or sham procedure. At t = 36 h, mean arterial pressure and aortic blood flow were measured, and blood and urine samples were obtained for biochemical determinations, including creatinine clearance, fractional excretion of sodium, and neutrophil gelatinase-associated lipocalin concentration in the urine. Kidney tissue samples were obtained for (i) light microscopy, (ii) immunofluorescence and Western blot for 3-nitrotyrosine and NOS2, (iii) gene expression (quantitative real-time polymerase chain reaction) studies (NOS1, NOS2, NOS3, and superoxide dismutase 1), and (iv) matrix-assisted laser desorption ionization time-of-flight mass spectrometry. Mean arterial pressure was unchanged and aortic blood flow decreased 25% in CLP animals. The sepsis-induced (i) decreased urine output and creatinine clearance and increased fractional excretion of sodium and urinary neutrophil gelatinase-associated lipocalin concentration, (ii) increased protein nitration and NOS2 protein, and (iii) NOS1 and NOS2 upregulation were all significantly attenuated by treatment with MnTMPyP or AG. Nitrated proteins in renal tissue from CLP animals (matrix-assisted laser desorption ionization time-of-flight mass spectrometry) were glutamate dehydrogenase, methylmalonate-semialdehyde dehydrogenase, and aldehyde dehydrogenase, mitochondrial proteins involved in energy metabolism or antioxidant defense. Nitro-oxidative stress is involved in sepsis-induced AKI, and protein nitration seems to be one mechanism involved.
authors: Departmento de Cuidados Intensivos, Hospital Universitario de Getafe, Madrid, Spain.
authors: Mariana
authors: M
authors: Seija
authors: Cecilia
authors: C
authors: Baccino
authors: Nicolás
authors: N
authors: Nin
authors: Carolina
authors: C
authors: Sánchez-Rodríguez
authors: Rosario
authors: R
authors: Granados
authors: Antonio
authors: A
authors: Ferruelo
authors: Leticia
authors: L
authors: Martínez-Caro
authors: Jesús
authors: J
authors: Ruíz-Cabello
authors: Marta
authors: M
authors: de Paula
authors: Oscar
authors: O
authors: Noboa
authors: Andrés
authors: A
authors: Esteban
authors: José Angel
authors: JA
authors: Lorente
mesh_terms: D058186:Acute Kidney Injury / Q000209:etiology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D000209:Acute-Phase Proteins / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D001783:Blood Flow Velocity / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006146:Guanidines / Q000494:pharmacology; D000071068:Lipocalin-2; D054834:Lipocalins / Q000378:metabolism; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D015513:Oncogene Proteins / Q000378:metabolism; D018384:Oxidative Stress; D030421:Peroxynitrous Acid / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D000209:Acute-Phase Proteins; D004791:Enzyme Inhibitors; D006146:Guanidines; D000071068:Lipocalin-2; D054834:Lipocalins; D008665:Metalloporphyrins; D015513:Oncogene Proteins; C071332:Lcn2 protein, mouse; D030421:Peroxynitrous Acid; C050950:tetrakis(N-methyl-4-pyridiniumyl)porphine manganese(III) complex; D019001:Nitric Oxide Synthase; C004479:pimagedine