Classical transient receptor potential channel 6 (TRPC6) is essential for ischemia‐reperfusion injury of the lung

Abstract

Lung endothelial damage is a characteristic feature of ischemia‐reperfusion (I/R) injury. However the molecular steps involved in the loss of endothelial integrity and subsequent invasion of immune cells are still poorly understood. Most notably, in isolated lungs from TRPC6‐deficient mice we observed a resistance to I/R injury, while lungs from wild‐type mice displayed pulmonary edema formation and organ dysfunction. To differentiate between the role of TRPC6 in circulating and/or resident leukocytes versus endothelial cells, TRPC6‐deficient bone marrow cells were transplanted into lethally irradiated wild‐type mice and vice versa. Based on these experiments in chimeric mice it is evident that endothelial but not leukocytic TRPC6 deficency protects from I/R injury of the lung. Therefore, pulmonary endothelial cells from wild‐type and TRPC6‐deficient mice were isolated and further analyzed. TRPC1, TRPC4 and TRPC6 were the predominantly expressed TRPC isoforms in these cells. Primary isolated endothelial cells from TRPC6‐deficient lungs show reduced ischemia‐induced Ca2+ influx and subsequent actin stress‐fiber formation as well as a decreased cellular shape change when compared to wild‐type cells. Thus, TRPC6 represents a promising novel pharmacological target to control critical early stages of I/R injury in the lung. Supported by the von‐Behring‐Röntgen Stiftung.