Role of TASK2 in the Control of Apoptotic Volume Decrease in Proximal Kidney Cells

J Biol Chem. 2007 Dec 14;282(50):36692-703. doi: 10.1074/jbc.M703933200. Epub 2007 Oct 18.

Abstract

Apoptotic volume decrease (AVD) is prerequisite to apoptotic events that lead to cell death. In a previous study, we demonstrated in kidney proximal cells that the TASK2 channel was involved in the K+ efflux that occurred during regulatory volume decrease. The aim of the present study was to determine the role of the TASK2 channel in the regulation of AVD and apoptosis phenomenon. For this purpose renal cells were immortalized from primary cultures of proximal convoluted tubules (PCT) from wild type and TASK2 knock-out mice (task2-/-). Apoptosis was induced by staurosporine, cyclosporin A, or tumor necrosis factor alpha. Cell volume, K+ conductance, caspase-3, and intracellular reactive oxygen species (ROS) levels were monitored during AVD. In wild type PCT cells the K+ conductance activated during AVD exhibited characteristics of TASK2 currents. In task2-/- PCT cells, AVD and caspase activation were reduced by 59%. Whole cell recordings indicated that large conductance calcium-activated K+ currents inhibited by iberiotoxin (BK channels) partially compensated for the deletion of TASK2 K+ currents in the task2-/- PCT cells. This result explained the residual AVD measured in these cells. In both cell lines, apoptosis was mediated via intracellular ROS increase. Moreover AVD, K+ conductances, and caspase-3 were strongly impaired by ROS scavenger N-acetylcysteine. In conclusion, the main K+ channels involved in staurosporine, cyclosporin A, and tumor necrosis factor-alpha-induced AVD are TASK2 K+ channels in proximal wild type cells and iberiotoxin-sensitive BK channels in proximal task2-/- cells. Both K+ channels could be activated by ROS production.

MeSH terms

  • Acetylcysteine / pharmacology
  • Animals
  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Calcium / metabolism
  • Caspase 3 / metabolism
  • Cell Line, Transformed
  • Cell Size* / drug effects
  • Cyclosporine / pharmacology
  • Enzyme Inhibitors / pharmacology
  • Free Radical Scavengers / pharmacology
  • Kidney Tubules, Proximal / cytology
  • Kidney Tubules, Proximal / metabolism*
  • Mice
  • Mice, Knockout
  • Peptides / pharmacology
  • Potassium / metabolism
  • Potassium Channels, Tandem Pore Domain / metabolism*
  • Reactive Oxygen Species / metabolism*
  • Staurosporine / pharmacology
  • Tumor Necrosis Factor-alpha / pharmacology

Substances

  • Enzyme Inhibitors
  • Free Radical Scavengers
  • Kcnk5 protein, mouse
  • Peptides
  • Potassium Channels, Tandem Pore Domain
  • Reactive Oxygen Species
  • Tumor Necrosis Factor-alpha
  • iberiotoxin
  • Cyclosporine
  • Casp3 protein, mouse
  • Caspase 3
  • Staurosporine
  • Potassium
  • Calcium
  • Acetylcysteine