Scientific article
Open access

Activation of TRPC6 channels is essential for lung ischaemia-reperfusion induced oedema in mice

Published inNature communications, vol. 3, 649
Publication date2012

Lung ischaemia-reperfusion-induced oedema (LIRE) is a life-threatening condition that causes pulmonary oedema induced by endothelial dysfunction. Here we show that lungs from mice lacking nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox2(y/-)) or the classical transient receptor potential channel 6 (TRPC6(-/-)) are protected from LIR-induced oedema (LIRE). Generation of chimeric mice by bone marrow cell transplantation and endothelial-specific Nox2 deletion showed that endothelial Nox2, but not leukocytic Nox2 or TRPC6, are responsible for LIRE. Lung endothelial cells from Nox2- or TRPC6-deficient mice showed attenuated ischaemia-induced Ca(2+) influx, cellular shape changes and impaired barrier function. Production of reactive oxygen species was completely abolished in Nox2(y/-) cells. A novel mechanistic model comprising endothelial Nox2-derived production of superoxide, activation of phospholipase C-γ, inhibition of diacylglycerol (DAG) kinase, DAG-mediated activation of TRPC6 and ensuing LIRE is supported by pharmacological and molecular evidence. This mechanism highlights novel pharmacological targets for the treatment of LIRE.

  • Animals
  • Calcium/metabolism
  • Diacylglycerol Kinase/metabolism
  • Edema/pathology/therapy
  • Endothelial Cells/cytology
  • Gene Deletion
  • Lung/pathology
  • Membrane Glycoproteins/genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Models, Biological
  • NADPH Oxidase/genetics
  • Permeability
  • Phospholipase C gamma/metabolism
  • Reactive Oxygen Species
  • Reperfusion Injury
  • TRPC Cation Channels/genetics
  • Time Factors
Citation (ISO format)
WEISSMANN, Norbert et al. Activation of TRPC6 channels is essential for lung ischaemia-reperfusion induced oedema in mice. In: Nature communications, 2012, vol. 3, p. 649. doi: 10.1038/ncomms1660
Main files (1)
Article (Published version)
ISSN of the journal2041-1723

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