title: Sodium nitrite potentiates renal oxidative stress and injury in hemoglobin exposed guinea pigs.
abstract: Methemoglobin-forming drugs, such as sodium nitrite (NaNO2), may exacerbate oxidative toxicity under certain chronic or acute hemolytic settings. In this study, we evaluated markers of renal oxidative stress and injury in guinea pigs exposed to extracellular hemoglobin (Hb) followed by NaNO2 at doses sufficient to simulate clinically relevant acute methemoglobinemia. NaNO2 induced rapid and extensive oxidation of plasma Hb in this model. This was accompanied by increased renal expression of the oxidative response effectors nuclear factor erythroid 2-derived-factor 2 (Nrf-2) and heme oxygenase-1 (HO-1), elevated non-heme iron deposition, lipid peroxidation, interstitial inflammatory cell activation, increased expression of tubular injury markers kidney injury-1 marker (KIM-1) and liver-fatty acid binding protein (L-FABP), podocyte injury, and cell death. Importantly, these indicators of renal oxidative stress and injury were minimal or absent following infusion of Hb or NaNO2 alone. Together, these results suggest that the exposure to NaNO2 in settings associated with increased extracellular Hb may potentiate acute renal toxicity via processes that are independent of NaNO2 induced erythrocyte methemoglobinemia.
authors.affiliation: Laboratory of Biochemistry and Vascular Biology, Division of Hematology Research and Review, Center for Biologics Evaluation and Research (CBER), U.S. Food and Drug Administration (FDA), Silver Spring, MD, USA.
authors.forename: Jin Hyen
authors.initials: JH
authors.lastname: Baek
authors.affiliation: Laboratory of Biochemistry and Vascular Biology, Division of Hematology Research and Review, Center for Biologics Evaluation and Research (CBER), U.S. Food and Drug Administration (FDA), Silver Spring, MD, USA.
authors.forename: Xiaoyuan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Laboratory of Biochemistry and Vascular Biology, Division of Hematology Research and Review, Center for Biologics Evaluation and Research (CBER), U.S. Food and Drug Administration (FDA), Silver Spring, MD, USA.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Williams
authors.affiliation: Laboratory of Biochemistry and Vascular Biology, Division of Hematology Research and Review, Center for Biologics Evaluation and Research (CBER), U.S. Food and Drug Administration (FDA), Silver Spring, MD, USA.
authors.forename: Wayne
authors.initials: W
authors.lastname: Hicks
authors.affiliation: Laboratory of Biochemistry and Vascular Biology, Division of Hematology Research and Review, Center for Biologics Evaluation and Research (CBER), U.S. Food and Drug Administration (FDA), Silver Spring, MD, USA.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Buehler
authors.affiliation: Laboratory of Biochemistry and Vascular Biology, Division of Hematology Research and Review, Center for Biologics Evaluation and Research (CBER), U.S. Food and Drug Administration (FDA), Silver Spring, MD, USA. Electronic address: felice.dagnillo@fda.hhs.gov.
authors.forename: Felice
authors.initials: F
authors.lastname: D'Agnillo
mesh_terms: D058186:Acute Kidney Injury / Q000097:blood / Q000139:chemically induced* / Q000473:pathology; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D050556:Fatty Acid-Binding Proteins / Q000378:metabolism; D006168:Guinea Pigs; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006454:Hemoglobins / Q000008:administration & dosage / Q000633:toxicity*; D007262:Infusions, Intravenous; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008706:Methemoglobin / Q000378:metabolism; D008708:Methemoglobinemia / Q000097:blood / Q000139:chemically induced* / Q000473:pathology; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D009566:Nitrates / Q000008:administration & dosage / Q000633:toxicity*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects*; D013997:Time Factors
chemical_list: D015415:Biomarkers; D050556:Fatty Acid-Binding Proteins; D006454:Hemoglobins; D051267:NF-E2-Related Factor 2; D009566:Nitrates; C031618:sodium nitrate; D008706:Methemoglobin; D051547:Heme Oxygenase-1
keywords: Biomarkers; Heme; Hemoglobin; Kidney; Nitrite; Oxidative stress