title: Treatment with p38 inhibitor intensifies the death of MG132-treated As4.1 juxtaglomerular cells via the enhancement of GSH depletion.
abstract: MG132, as a proteasome inhibitor, has been shown to induce apoptotic cell death through the formation of reactive oxygen species (ROS). In this study, we investigated the effects of MG132 and/or MAPK inhibitors on As4.1 juxtaglomerular cells in relation to cell growth, cell death, ROS, and glutathione (GSH) levels. MG132 inhibited the growth of As4.1 cells and induced cell death, accompanied by the loss of mitochondrial membrane potential (MMP; DeltaPsi(m)) and activation of caspase-3 and -8. MG132 increased ROS levels, and GSH depleted cell numbers. The MEK inhibitor slightly reduced cell growth and caspase-3 activity in MG132-treated As4.1 cells and mildly increased MMP (DeltaPsi(m)) loss and O(2)(*-) level. However, it did not increase apoptosis and GSH depletion. The JNK inhibitor did not strongly influence cell growth, cell death, and GSH depletion by MG132, but increased caspase-3 activity, MMP (DeltaPsi(m)) loss, and O(2)(*-) level. Treatment with the p38 inhibitor magnified cell-growth inhibition and apoptosis by MG132. This agent also strongly increased caspase-8 activity, MMP (DeltaPsi(m)) loss, O(2)(*-) level, and GSH depletion. Conclusively, the p38 inhibitor strongly intensified cell death in MG132-treated As4.1 cells. The changes of GSH content by MG132 and/or MAPK inhibitors were closely related to the death of As4.1 cells.
authors.affiliation: Department of Physiology, Medical School, Centers for Healthcare Technology Development, Institute for Medical Sciences, Chonbuk National University, JeonJu, Republic of Korea.
authors.forename: Yong Hwan
authors.initials: YH
authors.lastname: Han
authors.forename: Sung Zoo
authors.initials: SZ
authors.lastname: Kim
authors.forename: Suhn Hee
authors.initials: SH
authors.lastname: Kim
authors.forename: Woo Hyun
authors.initials: WH
authors.lastname: Park
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D005978:Glutathione / Q000378:metabolism*; D007606:Juxtaglomerular Apparatus / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D007976:Leupeptins / Q000494:pharmacology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D061988:Proteasome Inhibitors; D017382:Reactive Oxygen Species / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
chemical_list: D007976:Leupeptins; D061988:Proteasome Inhibitors; D017382:Reactive Oxygen Species; D048051:p38 Mitogen-Activated Protein Kinases; D053148:Caspase 3; D053181:Caspase 8; D005978:Glutathione; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde