Sodium channel Na _x is a regulator in epithelial sodium homeostasis

Abstract

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 Nax functions as a sodium sensor. With increased extracellular sodium, Nax 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. Nax is present in multiple epithelial tissues, and up-regulation of its downstream genes is found in hypertrophic scars. In animal models, blocking Nax 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 Nax in maintaining epithelial homeostasis.

Toll-Like Receptor Signaling in Burn Wound Healing and Scarring

“…The genes shown were upregulated in cultured keratinocytes in response to high sodium, dependent on the activity of the sodium channel Na x (scn7a). 28 incision wound edge, LTA-TLR2 signaling conversely stimulated cytokine production by other cell types in vitro: macrophages and dendritic and endothelial cells. 30 Thus, the activation of TLR2 signaling by skin flora might benefit or impair wound healing depending on the wound locale.…”

“…Water loss stays elevated long after reepithelialization of cutaneous wounds in general; for example, splitthickness skin-graft donor sites completed reepithelialization by postwound day 14, but water loss from the immature epidermis remained elevated for 200-400 days. 27 In addition, S100A12 was highly expressed in hypertrophic scar, 28 which occurs commonly after deep partial-thickness burns. And, S100A12 expression was elevated from postburn day 0-17 in the margins of partialthickness burn wounds in a clinical study 29 ( Fig.…”

Na+ homeostasis by epithelial Na+ channel (ENaC) and Nax channel (Nax): cooperation of ENaC and Nax

“…A further observation indicates that Na x regulates ENaC activity (46). As mentioned above, Na x acts as a sensor detecting the extracellular Na + concentration in the brain.…”

“…Thus, the low GFR due to a decrease in the circulating blood caused by low body Na + content increases renin release, leading to elevation of body Na + content due to an increase in Na + reabsorption via aldosterone-induced increases of ENaC production and surface expression in the collecting duct. Further, recently Na x has been reported to be a Na + concentration-sensitive Na + channel acting as a Na + sensor (46)(47)(48)(49)(50)(51)(52)(53)60,61). Na x was found in the brain as an atypical Na + channel, poorly homologous to the voltage-gated Na + channels (62).…”

“…When Na x detects an increased extracellular Na + concentration, Na x up-regulates prostasin (protease) release into the extracellular space (46), which activates ENaC by cleaving the extracellular loop of γ ENaC subunit (23,63), increasing Na + influx via ENaC associated with elevation of downstream mRNA synthesis of inflammatory mediators (46). Further, blockade of Na x expression improves scarring and atopic dermatitis (46). These findings strongly indicate that Na x plays an important role in maintaining epithelial homeostasis via control of ENaC activity.…”