title: Mechanism of paroxetine-induced cell death in renal tubular cells.
abstract: Paroxetine belongs to the family of selective serotonin reuptake inhibitors. Much research has been performed on the in vitro effect of paroxetine; however, the effect of paroxetine on Madin-Darby canine kidney renal tubular cells is unknown. The present study was aimed at exploring how paroxetine affects viability and to examine the underlying mechanisms. Paroxetine (15-200 microM) was shown to reduce cell viability via inducing apoptosis in a concentration-dependent manner. Paroxetine-induced cytotoxicity and apoptosis were not changed by the p38 mitogen-activated protein kinase inhibitor SB203580 and the c-Jun NH2-terminal kinase inhibitor SP600125, but was potentiated by the extracellular signal-regulated kinase inhibitor PD98059; inhibited by GF 109203X, a protein kinase C inhibitor; and potentiated by phorbol 12-myristate 13-acetate, a protein kinase C activator. Paroxetine induced [Ca2+](i) rises; however, pre-treatment with 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetra(acetoxymethyl)ester, a Ca2+ chelator, to prevent 20 microM paroxetine-induced [Ca2+](i) rises did not protect cells from death. H-89 (a protein kinase A inhibitor) and U73122 (a phospholipase C inhibitor) failed to alter paroxetine-induced cell death. The results suggest that in Madin-Darby canine kidney cells, paroxetine caused protein kinase C-dependent, Ca2+-independent apoptosis which was potentiated by inhibition of the extracellular signal-regulated kinase pathway.
authors.affiliation: Department of Surgery, Ping Tung Christian Hospital, Ping Tung, Taiwan.
authors.forename: Wei-Chuan
authors.initials: WC
authors.lastname: Chen
authors.forename: Chorng-Chih
authors.initials: CC
authors.lastname: Huang
authors.forename: Chun-Jen
authors.initials: CJ
authors.lastname: Huang
authors.forename: Jau-Min
authors.initials: JM
authors.lastname: Chien
authors.forename: Ko-Long
authors.initials: KL
authors.lastname: Lin
authors.forename: Yih-Chau
authors.initials: YC
authors.lastname: Lu
authors.forename: I-Shu
authors.initials: IS
authors.lastname: Chen
authors.forename: Shiuh-Inn
authors.initials: SI
authors.lastname: Liu
authors.forename: Shu-Shong
authors.initials: SS
authors.lastname: Hsu
authors.forename: Hong-Tai
authors.initials: HT
authors.lastname: Chang
authors.forename: Chiang-Ting
authors.initials: CT
authors.lastname: Chou
authors.forename: Chung-Ren
authors.initials: CR
authors.lastname: Jan
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism; D007684:Kidney Tubules / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D017374:Paroxetine / Q000008:administration & dosage / Q000633:toxicity*; D011493:Protein Kinase C / Q000187:drug effects / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000633:toxicity*; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism
chemical_list: D002118:Calcium; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D017374:Paroxetine; D011493:Protein Kinase C; D017367:Selective Serotonin Reuptake Inhibitors; D048051:p38 Mitogen-Activated Protein Kinases