title: Effect of reactive oxygen species on endothelin-1 production by human mesangial cells.
abstract: Reactive oxygen species (ROS) have been implicated in the pathophysiology of renal ischemia/reperfusion injury. Endothelin-1 (ET-1) is generated in abundance in renal ischemia/reperfusion with resultant decreases in renal blood flow and glomerular filtration rate. To determine if ROS regulate ET-1 production, the effect of ROS donors or scavengers on ET-1 protein and mRNA levels in cultured human mesangial cells was examined. Incubation with xanthine/xanthine oxidase, glucose oxidase, or H2O2 caused a dose-dependent rise in ET-1 release. Similarly, xanthine/xanthine oxidase or H2O2 augmented ET-1 mRNA levels. In contrast, the ROS scavengers dimethylthiourea (DMTU), dimethylpyrroline N-oxide, or pyrrolidine dithiocarbamate reduced basal ET-1 release, while DMTU lowered ET-1 mRNA levels. Deferoxamine, an iron chelator, also decreased basal ET-1 release. Superoxide dismutase potentiated the ET-1 stimulatory effect of xanthine/xanthine oxidase, while catalase abrogated the effect of xanthine/xanthine oxidase and H2O2. The effects of ROS were unrelated to changes in nitric oxide production or cytotoxicity. These data indicate that exogenously or endogenously-derived ROS can increase ET-1 production by human mesangial cells. While superoxide anion reduces ET-1 levels, H2O2 leads to enhanced production of the peptide. ROS stimulation of mesangial cell ET-1 production may contribute to impaired glomerular hemodynamics in the setting of renal ischemia/reperfusion injury.
authors.affiliation: Department of Medicine, Veterans Affairs Medical Center, Salt Lake City, Utah, USA.
authors.forename: A K
authors.initials: AK
authors.lastname: Hughes
authors.forename: P K
authors.initials: PK
authors.lastname: Stricklett
authors.forename: E
authors.initials: E
authors.lastname: Padilla
authors.forename: D E
authors.initials: DE
authors.lastname: Kohan
mesh_terms: D001483:Base Sequence; D006152:Cyclic GMP / Q000378:metabolism; D019332:Endothelin-1 / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics; D005920:Glomerular Mesangium / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008969:Molecular Sequence Data; D009569:Nitric Oxide / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism*; D017382:Reactive Oxygen Species; D014407:Tumor Cells, Cultured
chemical_list: D019332:Endothelin-1; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D006152:Cyclic GMP