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

Norbert Weissmann (), Akylbek Sydykov, Hermann Kalwa, Ursula Storch, Beate Fuchs, Michael Mederos y Schnitzler, Ralf P. Brandes, Friedrich Grimminger, Marcel Meissner, Marc Freichel, Stefan Offermanns, Florian Veit, Oleg Pak, Karl-Heinz Krause, Ralph T. Schermuly, Alison C Brewer, Harald H.H.W. Schmidt, Werner Seeger, Ajay M. Shah, Thomas Gudermann, Hossein A. Ghofrani and Alexander Dietrich ()
Additional contact information
Norbert Weissmann: University of Giessen Lung Center (UGLC), Klinikstrasse 36, 35392 Giessen, Germany.
Akylbek Sydykov: University of Giessen Lung Center (UGLC), Klinikstrasse 36, 35392 Giessen, Germany.
Hermann Kalwa: Institute of Pharmacology and Toxicology, School of Medicine, University of Marburg, Karl-von-Frisch-Street 1, 35033 Marburg, Germany.
Ursula Storch: Walther-Straub-Institute of Pharmacology and Toxicology, University of Munich, Nußbaumstrasse 26 and Goethestrasse 33, 80336 Munich, Germany.
Beate Fuchs: University of Giessen Lung Center (UGLC), Klinikstrasse 36, 35392 Giessen, Germany.
Michael Mederos y Schnitzler: Walther-Straub-Institute of Pharmacology and Toxicology, University of Munich, Nußbaumstrasse 26 and Goethestrasse 33, 80336 Munich, Germany.
Ralf P. Brandes: Vascular Research Center, Medical Faculty, J.W. Goethe University Frankfurt, Theodor-Stern Kai 7, 60596 Frankfurt/Main, Germany.
Friedrich Grimminger: University of Giessen Lung Center (UGLC), Klinikstrasse 36, 35392 Giessen, Germany.
Marcel Meissner: Experimental and Clinical Pharmacology, Medical Faculty, University of the Saarland, Universitätskliniken Geb. 46
Marc Freichel: Experimental and Clinical Pharmacology, Medical Faculty, University of the Saarland, Universitätskliniken Geb. 46
Stefan Offermanns: Max-Planck-Institut für Herz und Lungenforschung, Ludwigsstrasse 43, 61231 Bad Nauheim, Germany.
Florian Veit: University of Giessen Lung Center (UGLC), Klinikstrasse 36, 35392 Giessen, Germany.
Oleg Pak: University of Giessen Lung Center (UGLC), Klinikstrasse 36, 35392 Giessen, Germany.
Karl-Heinz Krause: Geneva Faculty of Medicine, Centre Médical Universitaire, 1, rue Michel-Servet, 1211 Geneva 4, Switzerland.
Ralph T. Schermuly: University of Giessen Lung Center (UGLC), Klinikstrasse 36, 35392 Giessen, Germany.
Alison C Brewer: King's College London British Heart Foundation Centre
Harald H.H.W. Schmidt: Universiteitssingel 50, 6229 ER Maastricht, 6200 MD Maastricht, The Netherlands.
Werner Seeger: University of Giessen Lung Center (UGLC), Klinikstrasse 36, 35392 Giessen, Germany.
Ajay M. Shah: King's College London British Heart Foundation Centre
Thomas Gudermann: Walther-Straub-Institute of Pharmacology and Toxicology, University of Munich, Nußbaumstrasse 26 and Goethestrasse 33, 80336 Munich, Germany.
Hossein A. Ghofrani: University of Giessen Lung Center (UGLC), Klinikstrasse 36, 35392 Giessen, Germany.
Alexander Dietrich: Walther-Straub-Institute of Pharmacology and Toxicology, University of Munich, Nußbaumstrasse 26 and Goethestrasse 33, 80336 Munich, Germany.

Nature Communications, 2012, vol. 3, issue 1, 1-10

Abstract: 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 (Nox2y/−) 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 Ca2+ influx, cellular shape changes and impaired barrier function. Production of reactive oxygen species was completely abolished in Nox2y/− 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.

Date: 2012
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DOI: 10.1038/ncomms1660

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