Postnatal Requirement of the Epithelial Sodium Channel for Maintenance of Epidermal Barrier Function

Charles, Roch‐Philippe; Guitard, Marjorie; Leyvraz, Céline; Breiden, Bernadette; Haftek, Marek; Haftek-Terreau, Zofia; Stehle, Jean-Christophe; Sandhoff, Konrad; Hummler, Edith

doi:10.1074/jbc.m708829200

Cited by 40 publications

(35 citation statements)

References 64 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…7,9 ␣ENaC deficiency also induces death shortly after birth, with a lung, skin, and kidney phenotype. 8,18 Mice in which ␣ENaC is deleted specifically in the CD are viable and do not show disturbances in sodium and potassium balance even when subjected to challenging diets. 10 This suggested that the CNT is important in controlling ENaC-mediated sodium reabsorption in the kidney.…”

Section: Discussionmentioning

confidence: 99%

Sodium and Potassium Balance Depends on αENaC Expression in Connecting Tubule

Christensen¹,

Perrier²,

Wang

et al. 2010

Journal of the American Society of Nephrology

Self Cite

View full text Add to dashboard Cite

Mutations in ␣, ␤, or ␥ subunits of the epithelial sodium channel (ENaC) can downregulate ENaC activity and cause a severe salt-losing syndrome with hyperkalemia and metabolic acidosis, designated pseudohypoaldosteronism type 1 in humans. In contrast, mice with selective inactivation of ␣ENaC in the collecting duct (CD) maintain sodium and potassium balance, suggesting that the late distal convoluted tubule (DCT2) and/or the connecting tubule (CNT) participates in sodium homeostasis. To investigate the relative importance of ENaC-mediated sodium absorption in the CNT, we used Cre-lox technology to generate mice lacking ␣ENaC in the aquaporin 2-expressing CNT and CD. Western blot analysis of microdissected cortical CD (CCD) and CNT revealed absence of ␣ENaC in the CCD and weak ␣ENaC expression in the CNT. These mice exhibited a significantly higher urinary sodium excretion, a lower urine osmolality, and an increased urine volume compared with control mice. Furthermore, serum sodium was lower and potassium levels were higher in the genetically modified mice. With dietary sodium restriction, these mice experienced significant weight loss, increased urinary sodium excretion, and hyperkalemia. Plasma aldosterone levels were significantly elevated under both standard and sodium-restricted diets. In summary, ␣ENaC expression within the CNT/CD is crucial for sodium and potassium homeostasis and causes signs and symptoms of pseudohypoaldosteronism type 1 if missing.

show abstract

Section: Discussionmentioning

confidence: 99%

Sodium and Potassium Balance Depends on αENaC Expression in Connecting Tubule

Christensen¹,

Perrier²,

Wang

et al. 2010

Journal of the American Society of Nephrology

Self Cite

View full text Add to dashboard Cite

show abstract

“…Thus, we propose that ENaC-mediated sensing of the EF plays a fundamental physiologic role in directing cell migration and contributing to wound repair. Additionally this work describes a novel role for ENaC in the epidermis, beyond the previously described function of modulating epidermal barrier formation (Charles et al, 2008).…”

Section: Enac Protein Mediates Galvanotaxismentioning

confidence: 99%

“…Although the genetic ablation of the aENaC gene in mice results in a postnatal lethal phenotype due to an inability to clear lung fluids (Hummler et al, 1996), the role of this channel in skin epithelial biology is not yet elucidated. aENaC knockout mice do have abnormal lipid composition in their stratum corneum (Mauro et al, 2002;Charles et al, 2008), but these animals do not survive long enough to perform in vivo skin investigations. In humans, loss-offunction mutations of aENaC genes cause a rare autosomal, recessive disease: pseudohypoaldosteronism type 1 (Chang et al, 1996;Strautnieks et al, 1996), resulting in salt loss, hyperkalemia and metabolic acidosis in newborns.…”

Section: Introductionmentioning

confidence: 99%

The epithelial sodium channel mediates the directionality of galvanotaxis in human keratinocytes

Yang

Charles

Hummler

et al. 2013

Journal of Cell Science

Self Cite

View full text Add to dashboard Cite

SummaryCellular directional migration in an electric field (galvanotaxis) is one of the mechanisms guiding cell movement in embryogenesis and in skin epidermal repair. The epithelial sodium channel (ENaC), in addition to its function of regulating sodium transport in kidney, has recently been found to modulate cell locomotory speed. Here we tested whether ENaC has an additional function of mediating the directional migration of galvanotaxis in keratinocytes. Genetic depletion of ENaC completely blocks only galvanotaxis and does not decrease migration speed. Overexpression of ENaC is sufficient to drive galvanotaxis in otherwise unresponsive cells. Pharmacologic blockade or maintenance of the open state of ENaC also decreases or increases, respectively, galvanotaxis, suggesting that the channel open state is responsible for the response. Stable lamellipodial extensions formed at the cathodal sides of wild-type cells at the start of galvanotaxis; these were absent in the ENaC knockout keratinocytes, suggesting that ENaC mediates galvanotaxis by generating stable lamellipodia that steer cell migration. We provide evidence that ENaC is required for directional migration of keratinocytes in an electric field, supporting a role for ENaC in skin wound healing.

show abstract

“…In these epithelia ENaC is the rate-limiting step for sodium absorption and plays a critical role in the maintenance of body sodium balance (1)(2)(3)(4). In addition, ENaC expression has been reported in a number of other tissues, including skin, endothelial cells, vascular smooth muscle cells, and neurons where its physiological role remains to be determined (5)(6)(7)(8)(9)(10)(11)(12).…”

mentioning

confidence: 99%

The δ-Subunit of the Epithelial Sodium Channel (ENaC) Enhances Channel Activity and Alters Proteolytic ENaC Activation

Haerteis

Krueger

Korbmacher

et al. 2009

Journal of Biological Chemistry

View full text Add to dashboard Cite

The epithelial sodium channel (ENaC) is probably a heterotrimer with three well characterized subunits (␣␤␥). In humans an additional ␦-subunit (␦-hENaC) exists but little is known about its function. Using the Xenopus laevis oocyte expression system, we compared the functional properties of ␣␤␥-and ␦␤␥-hENaC and investigated whether ␦␤␥-hENaC can be proteolytically activated. The amiloride-sensitive ENaC whole-cell current (⌬I ami ) was about 11-fold larger in oocytes expressing ␦␤␥-hENaC than in oocytes expressing ␣␤␥-hENaC. The 2-fold larger single-channel Na ؉ conductance of ␦␤␥-hENaC cannot explain this difference. Using a chemiluminescence assay, we demonstrated that an increased channel surface expression is also not the cause. Thus, overall channel activity of ␦␤␥-hENaC must be higher than that of ␣␤␥-hENaC. Experiments exploiting the properties of the known ␤S520C mutant ENaC confirmed this conclusion. Moreover, chymotrypsin had a reduced stimulatory effect on ␦␤␥-hENaC whole-cell currents compared with its effect on ␣␤␥-hENaC whole-cell currents (2-fold versus 5-fold). This suggests that the cell surface pool of so-called near-silent channels that can be proteolytically activated is smaller for ␦␤␥-hENaC than for ␣␤␥-hENaC. Proteolytic activation of ␦␤␥-hENaC was associated with the appearance of a ␦-hENaC cleavage product at the cell surface. Finally, we demonstrated that a short inhibitory 13-mer peptide corresponding to a region of the extracellular loop of human ␣-ENaC inhibited ⌬I ami in oocytes expressing ␣␤␥-hENaC but not in those expressing ␦␤␥-hENaC. We conclude that the ␦-subunit of ENaC alters proteolytic channel activation and enhances base-line channel activity.

show abstract

Postnatal Requirement of the Epithelial Sodium Channel for Maintenance of Epidermal Barrier Function

Cited by 40 publications

References 64 publications

Sodium and Potassium Balance Depends on αENaC Expression in Connecting Tubule

Sodium and Potassium Balance Depends on αENaC Expression in Connecting Tubule

The epithelial sodium channel mediates the directionality of galvanotaxis in human keratinocytes

The δ-Subunit of the Epithelial Sodium Channel (ENaC) Enhances Channel Activity and Alters Proteolytic ENaC Activation

Contact Info

Product

Resources

About