Nonselective cation channels as effectors of free radical-induced rat liver cell necrosis

Luis Felipe Barros, Andrés Stutzin, Andrea Calixto, Marcelo Catalán, Joel Castro, Claudio Hetz, Tamara Hermosilla

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Abstract

Necrosis, as opposed to apoptosis, is recognized as a non-specific cell death that induces tissue inflammation and is preceded by cell edema. In non-neuronal cells, the latter has been explained by defective outward pumping of Na+caused by metabolic depletion or by increased Na+influx via membrane transporters. Here we describe a novel mechanism of swelling and necrosis; namely the influx of Na+through oxidative stress-activated nonselective cation channels. Exposure of liver epithelial Clone 9 cells to the free-radical donors calphostin C or menadione induced the rapid activation of an approximately 16-pS nonselective cation channel (NSCC). Blockage of this conductance with flufenamic acid protected the cells against swelling, calcium overload, and necrosis. Protection was also achieved by Gd3+, an inhibitor of stretch-activated cation channels, or by isosmotic replacement of extracellular Na+with N-methyl-D-glucamine. It is proposed that NSCCs, which are ubiquitous although largely inactive in healthy cells, become activated under severe oxidative stress. The ensuing influx of Na+initiates a positive feedback of metabolic and electrolytic disturbances leading cells to their necrotic demise.

Original languageEnglish
Pages (from-to)114-122
Number of pages9
JournalHepatology
Volume33
Issue number1
DOIs
Publication statusPublished - 1 Jan 2001
Externally publishedYes

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    Barros, L. F., Stutzin, A., Calixto, A., Catalán, M., Castro, J., Hetz, C., & Hermosilla, T. (2001). Nonselective cation channels as effectors of free radical-induced rat liver cell necrosis. Hepatology, 33(1), 114-122. https://doi.org/10.1053/jhep.2001.20530