PGE(2)-MEDIATED CYTOPROTECTION IN RENAL EPITHELIAL-CELLS - EVIDENCE FOR A PHARMACOLOGICALLY DISTINCT RECEPTOR

Although the exact mechanism of prostaglandin E-2 (PGE(2))-mediated cy toprotection has not been elucidated, its ability to induce cytoprotec tion in cell culture suggests this action occurs at the cellular level . The present studies were conducted to determine whether PGE(2) induc es protection against 2,3,5-(trisglutathion-S-yl)-hydroquinone [2,3,5- (trisglutathion-S-yl)-HQ]-mediated cytotoxicity in a renal proximal tu bule epithelial cell line (LLC-PK1) and to delineate the cellular and molecular mechanisms associated with this response. Pretreatment of LL C-PK1 cells with 0.01-40 mu M PGE(2) for 24 h fully protects against a moderately toxic concentration of 2,3,5-(trisglutathion-S-yl)-HQ. PGE (2)-mediated cytoprotection is observed in cells pretreated at pH 7.4 but not at pH 7.8. However, cytoprotection is observed in LLC-PK1 cell s pretreated with the PGE(2) analog, 11-deoxy-16,16-dimethyl PGE(2) (D DM-PGE(2)) but not with the PGE(2) receptor [E-prostanoid (EP)] agonis ts 17-phenyltrinor PGE(2) (EP1), Il-deoxy PGE(1) (EP2/EP4), sulproston e (EP1/EP3), PGE(1), or PGA(2). 12-O-tetradecanoylphorbol-13-acetate ( TPA), a potent activator of protein kinase C (PKC), also induces cytop rotection, supporting a role for this pathway in the cytoprotective re sponse. PGE(2), DDM-PGE(2), and TPA all induce the binding of nuclear proteins to a TPA responsive element (TRE), whereas analogs that did n ot induce cytoprotection (PGE(1), 17-phenyltrinor PGE(2), sulprostone) were without effect. DDM-PGE(2)- and TPA-mediated cytoprotection and TRE binding activity are inhibited by -propenyl]-amino}-ethyl)-5-isoqu inolinesulfonamide (H-89), a PKC inhibitor These data suggest that cyt oprotection by PGE(2) and DDM-PGE(2) in LLC-PK1 cells is mediated by a PKC-coupled receptor, which is pharmacologically distinct from the pr esently classified EP receptor subtypes.