An indispensable role of TRPC6‐mediated Ca2+ entry in increasing lung microvascular permeability and acute lung injury

Abstract

Studies have shown that transient receptor potential cation channels (TRPC) form the principal mechanism to increase intracellular Ca2+ in several cell types including endothelial cells. We showed that thrombin by binding to its receptor PAR‐1 activates transient receptor potential channel 6 (TRPC6), a receptor‐operated Ca2+ channel (ROC), which in turn regulates RhoA‐induced endothelial contraction. In the present study we have investigated microvascular permeability response and lung edema formation in the TRPC6−/− mice. We isolated lungs from TRPC6−/− mice and from strain‐matched wild type (WT) mice and determined the filtration co‐efficient (Kf, c), a measure of hydraulic conductivity across endothelial exchange barrier in response to oleoyl‐2‐acetyl‐sn glycerol (OAG), a cell‐membrane permeable analog of DAG and PAR‐1 peptide. OAG and PAR‐1 increased Kf, c in lungs from WT mice whereas they failed to increase Kf, c in lungs isolated from TRPC6−/− mice. TRPC6 transcript expression was detected in lungs from WT mice but not from TRPC6−/− mouse. Expression of TRPC3, another ROC or TRPC1, a SOC was not altered in TRPC6−/− mice lungs. We also determined endotoxin LPS‐induced acute lung injury (ALI) in WT and TRPC6−/− mice by determining lung wet to dry weight ratio and albumin permeability across the lung microcirculation. We observed that LPS induced lung edema was markedly reduced in TRPC6−/− mice. These intriguing findings suggest that TRPC6 activity is essentially required for increasing lung microvascular permeability and ALI.