title: PGE2-mediated cytoprotection in renal epithelial cells: evidence for a pharmacologically distinct receptor.
abstract: Although the exact mechanism of prostaglandin E2 (PGE2)-mediated cytoprotection has not been elucidated, its ability to induce cytoprotection in cell culture suggests this action occurs at the cellular level. The present studies were conducted to determine whether PGE2 induces protection against 2,3,5-(trisglutathion-S-yl)-hydroquinone [2,3,5-(trisglutathion-S-yl)-HQ]-mediated cytotoxicity in a renal proximal tubule epithelial cell line (LLC-PK1) and to delineate the cellular and molecular mechanisms associated with this response. Pretreatment of LLC-PK1 cells with 0.01-40 microM PGE2 for 24 h fully protects against a moderately toxic concentration of 2,3,5-(trisglutathion-S-yl)-HQ. PGE2-mediated cytoprotection is observed in cells pretreated at pH 7.4 but not at pH 7.8. However, cytoprotection is observed in LLC-PK1 cells pretreated with the PGE2 analog, 11-deoxy-16,16-dimethyl PGE2 (DDM-PGE2) but not with the PGE2 receptor [E-prostanoid (EP)] agonists 17-phenyltrinor PGE2 (EP1), 11-deoxy PGE1 (EP2/EP4), sulprostone (EP1/EP3), PGE1, or PGA2. 12-O-tetradecanoylphorbol-13-acetate (TPA), a potent activator of protein kinase C (PKC), also induces cytoprotection, supporting a role for this pathway in the cytoprotective response. PGE2, DDM-PGE2, and TPA all induce the binding of nuclear proteins to a TPA responsive element (TRE), whereas analogs that did not induce cytoprotection (PGE1, 17-phenyltrinor PGE2, sulprostone) were without effect. DDM-PGE2- and TPA-mediated cytoprotection and TRE binding activity are inhibited by N-(2[[3-(4-bromophenyl)-2-propenyl]-amino]-ethyl)-5-isoquinolinesulfonam ide (H-89), a PKC inhibitor. These data suggest that cytoprotection by PGE2 and DDM-PGE2 in LLC-PK1 cells is mediated by a PKC-coupled receptor, which is pharmacologically distinct from the presently classified EP receptor subtypes.
authors.affiliation: Division of Pharmacology and Toxicology, College of Pharmacy, University of Texas at Austin, 78712-1074, USA.
authors.forename: T J
authors.initials: TJ
authors.lastname: Weber
authors.forename: T J
authors.initials: TJ
authors.lastname: Monks
authors.forename: S S
authors.initials: SS
authors.lastname: Lau
mesh_terms: D015064:16,16-Dimethylprostaglandin E2 / Q000031:analogs & derivatives; D000818:Animals; D019610:Cytoprotection / Q000502:physiology*; D015232:Dinoprostone / Q000494:pharmacology / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects / Q000502:physiology; D005978:Glutathione / Q000031:analogs & derivatives / Q000494:pharmacology; D006873:Hydroquinones / Q000494:pharmacology; D007668:Kidney / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D018374:LLC-PK1 Cells; D011493:Protein Kinase C / Q000378:metabolism; D018078:Receptors, Prostaglandin E / Q000819:agonists / Q000145:classification / Q000502:physiology; D013552:Swine; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
chemical_list: D006873:Hydroquinones; D018078:Receptors, Prostaglandin E; C078765:2,3,5-(triglutathion-S-yl)hydroquinone; D011493:Protein Kinase C; D005978:Glutathione; D015232:Dinoprostone; D015064:16,16-Dimethylprostaglandin E2; D013755:Tetradecanoylphorbol Acetate