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The mechanisms by which the epidermis responds to disturbances in barrier function and restores homeostasis are unknown. With a perturbation of the epidermal barrier, water is lost, resulting in an increase in extracellular sodium concentration. We demonstrate that the sodium channel Na_x functions as a sodium sensor. With increased extracellular sodium, Na_x up-regulates prostasin, which results in activation of the sodium channel ENaC, resulting in increased sodium flux and increased downstream mRNA synthesis of inflammatory mediators. Na_x is present in multiple epithelial tissues, and up-regulation of its downstream genes is found in hypertrophic scars. In animal models, blocking Na_x expression results in improvement in scarring and atopic dermatitis–like symptoms, both of which are pathological conditions characterized by perturbations in barrier function. These findings support an important role for Na …