title: Multiple cell death pathways are independently activated by lethal hypertonicity in renal epithelial cells.
abstract: When hypertonicity is imposed with sufficient intensity and acuteness, cells die. Here we investigated the cellular pathways involved in death using a cell line derived from renal epithelium. We found that hypertonicity rapidly induced activation of an intrinsic cell death pathway-release of cytochrome c and activation of caspase-3 and caspase-9-and an extrinsic pathway-activation of caspase-8. Likewise, a lysosomal pathway of cell death characterized by partial lysosomal rupture and release of cathepsin B from lysosomes to the cytosol was also activated. Relationships among the pathways were examined using specific inhibitors. Caspase inhibitors did not affect cathepsin B release into the cytosol by hypertonicity. In addition, cathepsin B inhibitors and caspase inhibitors did not affect hypertonicity-induced cytochrome c release, suggesting that the three pathways were independently activated. Combined inhibition of caspases and cathepsin B conferred significantly more protection from hypertonicity-induced cell death than inhibition of caspase or cathepsin B alone, indicating that all the three pathways contributed to the hypertonicity-induced cell death. Similar pattern of sensitivity to the inhibitors was observed in two other cell lines derived from renal epithelia. We conclude that multiple cell death pathways are independently activated early in response to lethal hypertonic stress in renal epithelial cells.
authors.affiliation: Department of Biological Science, Ulsan National Institute of Science and Technology, Ulsan, Korea; and.
authors.forename: Soo Youn
authors.initials: SY
authors.lastname: Choi
authors.forename: Whaseon
authors.initials: W
authors.lastname: Lee-Kwon
authors.forename: Hwan Hee
authors.initials: HH
authors.lastname: Lee
authors.forename: Jun Ho
authors.initials: JH
authors.lastname: Lee
authors.forename: Satoru
authors.initials: S
authors.lastname: Sanada
authors.forename: Hyug Moo
authors.initials: HM
authors.lastname: Kwon
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D061945:Caspase Inhibitors / Q000494:pharmacology; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D002401:Cathepsin B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000502:physiology*; D045304:Cytochromes c / Q000235:genetics / Q000378:metabolism; D004285:Dogs; D004847:Epithelial Cells / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D007668:Kidney / Q000166:cytology*; D051379:Mice
chemical_list: D061945:Caspase Inhibitors; D045304:Cytochromes c; D020169:Caspases; D002401:Cathepsin B
keywords: caspase; cathepsin B; cytochrome c