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

Nat Commun. 2012 Jan 31;3:649. doi: 10.1038/ncomms1660.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism
  • Diacylglycerol Kinase / metabolism
  • Edema / pathology
  • Edema / therapy*
  • Endothelial Cells / cytology
  • Gene Deletion
  • Lung / pathology*
  • Membrane Glycoproteins / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Models, Biological
  • NADPH Oxidase 2
  • NADPH Oxidases / genetics
  • Permeability
  • Phospholipase C gamma / metabolism
  • Reactive Oxygen Species
  • Reperfusion Injury*
  • TRPC Cation Channels / genetics*
  • Time Factors

Substances

  • Membrane Glycoproteins
  • Reactive Oxygen Species
  • TRPC Cation Channels
  • Trpc6 protein, mouse
  • Cybb protein, mouse
  • NADPH Oxidase 2
  • NADPH Oxidases
  • Diacylglycerol Kinase
  • Phospholipase C gamma
  • Calcium