Up‐regulation of airway epithelial sodium channels in urokinase plasminogen activator receptor (uPAR) deficient mice

Abstract

The urokinase plasminogen activator receptor (uPAR) is a key receptor involved in plasminogen activation and other non-proteolytical processes. Depression of fibrinolysis has been implicated in edematous acute lung injury and acute respiratory distress syndrome. Salt resolution through epithelial sodium channels (ENaC) is a determinant pathway for alveolar fluid clearance. We hypothesized that uPAR may alter alveolar fluid clearance by regulating ENaC expression and function. The survival rate of influenza (H1N1 A/PR/8/34) infected mice is much greater for uPAR homozygotes (60 %) than that for wild type C57/B6 mice (20 %, n=11, P<0.05). In primary mouse tracheal epithelial cells, ENaC expression at the transcriptional level, as determined by real-time RT-PCR, is significantly increased by 172 ± 38 % and 39 ± 13 %, respectively, for β and γ ENaC subunits (n=4, P<0.05). In addition, α ENaC shows a slight increment (16%). Moreover, ENaC-associated short-circuit current is 32.4 ± 5.8 μA/cm2 (n=5) in primary mouse tracheal epithelial monolayer cells isolated from uPAR deficient mice, which is much greater than that of age- and sex-matched wild type mice (20.2 ± 2.4 μA/cm2, n=9, P<0.05). These observations suggest that uPAR may serve as an inhibitory regulator to down-regulate ENaC in primary mouse tracheal epithelial cells. Supported by NIH grants HL87017 and HL95435.