Deficiency of urokinase plasminogen activator suppresses epithelial sodium channels in tracheal epithelial cells

Abstract

Epithelial sodium channels (ENaC) govern transepithelial salt and fluid transport in tracheal, bronchi, and lungs. Fibrinolytic proteases play a crucial role in airway and lung injury and repair. We hypothesized that urokinase‐like plasminogen activator (uPA) regulates respiratory ENaC activity in primary mouse tracheal epithelial cells. The short‐circuit currents in confluent monolayer cells were compared between wild type and uPA null mice. Knockout of uPA led to depressed ENaC activity in both intact and permeabilized cells significantly. A significant decrease in Na+/K+‐ATPase activity was observed as well. Application of uPA and plasmin partially restored ENaC activity and increased cleavage of alpha ENaC proteins in confluent monolayers. ERK1/2 but not Akt phosphorylation was augmented in uPA−/− cells and lungs. Taken together, uPA may regulate ENaC activity via multifaceted mechanisms, including proteolytic cleavage of α ENaC proteins, reduction in vectorial Na+ driving force, and upregulation of ERK1/2 phosphorylation.Supported by NIH HL87017 and HL95435