Mechanism of paroxetine-induced cell death in renal tubular cells.
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.
Chen
Wei-Chuan
WC
Department of Surgery, Ping Tung Christian Hospital, Ping Tung, Taiwan.
Huang
Chorng-Chih
CC
Huang
Chun-Jen
CJ
Chien
Jau-Min
JM
Lin
Ko-Long
KL
Lu
Yih-Chau
YC
Chen
I-Shu
IS
Liu
Shiuh-Inn
SI
Hsu
Shu-Shong
SS
Chang
Hong-Tai
HT
Chou
Chiang-Ting
CT
Jan
Chung-Ren
CR
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
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