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

Abstract

In skin, the physiological consequence of an epithelial sodium channel (ENaC) deficiency is not obvious directly at birth. Nevertheless, within hours after birth, mice deficient for the α-subunit of the highly amiloride-sensitive epithelial sodium channel (αENaC/Scnn1a) suffer from a significant increased dehydration. This is characterized by a loss of body weight (by 6% in 6 h) and an increased transepidermal water loss, which is accompanied by a higher skin surface pH in 1-day-old pups. Although early and late differentiation markers, as well as tight junction protein distribution and function, seem unaffected, deficiency of αENaC severely disturbs the stratum corneum lipid composition with decreased ceramide and cholesterol levels, and increased pro-barrier lipids, whereas covalently bound lipids are drastically reduced. Ultrastructural analysis revealed morphological changes in the formation of intercellular lamellar lipids and the lamellar body secretion. Extracellular formation of the lamellar lipids proved to be abnormal in the knockouts. In conclusion, ENaC deficiency results in progressive dehydration and, consequently, weight loss due to severe impairment of lipid formation and secretion. Our data demonstrate that ENaC expression is required for the postnatal maintenance of the epidermal barrier function but not for its generation. In skin, the physiological consequence of an epithelial sodium channel (ENaC) deficiency is not obvious directly at birth. Nevertheless, within hours after birth, mice deficient for the α-subunit of the highly amiloride-sensitive epithelial sodium channel (αENaC/Scnn1a) suffer from a significant increased dehydration. This is characterized by a loss of body weight (by 6% in 6 h) and an increased transepidermal water loss, which is accompanied by a higher skin surface pH in 1-day-old pups. Although early and late differentiation markers, as well as tight junction protein distribution and function, seem unaffected, deficiency of αENaC severely disturbs the stratum corneum lipid composition with decreased ceramide and cholesterol levels, and increased pro-barrier lipids, whereas covalently bound lipids are drastically reduced. Ultrastructural analysis revealed morphological changes in the formation of intercellular lamellar lipids and the lamellar body secretion. Extracellular formation of the lamellar lipids proved to be abnormal in the knockouts. In conclusion, ENaC deficiency results in progressive dehydration and, consequently, weight loss due to severe impairment of lipid formation and secretion. Our data demonstrate that ENaC expression is required for the postnatal maintenance of the epidermal barrier function but not for its generation. The highly amiloride-sensitive epithelial sodium channel (ENaC) 3The abbreviations used are: ENaCepithelial sodium channelPBSphosphate-buffered salineTEWLtransepidermal water lossDAPI4′,6-diamidino-2-phenylindoleSGstratum granulosumSPstratum spinosumSCstratum corneumCerceramide. 3The abbreviations used are: ENaCepithelial sodium channelPBSphosphate-buffered salineTEWLtransepidermal water lossDAPI4′,6-diamidino-2-phenylindoleSGstratum granulosumSPstratum spinosumSCstratum corneumCerceramide. is a membrane constituent of many salt-absorbing epithelia. It facilitates Na+ movement across tight epithelia and is therefore involved in whole net sodium ion balance of the body (1Hummler E. Vallon V. J. Am. Soc. Nephrol. 2005; 16: 3160-3166Crossref PubMed Scopus (29) Google Scholar). ENaC is a member of the superfamily of ion channels implicated in mechanoperception and acid sensing (2Kellenberger S. Schild L. Physiol. Rev. 2002; 82: 735-767Crossref PubMed Scopus (839) Google Scholar). It is composed of three highly homologous subunits (α-, β-, and γENaC) encoding Scnn1a, Scnn1b, and Scnn1g and characterized in several species, including man and mouse (3Canessa C.M. Horisberger J.D. Rossier B.C. Nature. 1993; 361: 467-470Crossref PubMed Scopus (816) Google Scholar, 4Canessa C.M. Schild L. Buell G. Thorens B. Gautschi I. Horisberger J.D. Rossier B.C. Nature. 1994; 367: 463-467Crossref PubMed Scopus (1739) Google Scholar, 5Rossier B.C. Pradervand S. Schild L. Hummler E. Ann. Rev. Physiol. 2002; 64: 877-897Crossref PubMed Scopus (309) Google Scholar). In vitro experiments clearly demonstrate that, in the absence of the α-subunit, channels made of β- and γ-subunits alone do not confer ENaC activity (4Canessa C.M. Schild L. Buell G. Thorens B. Gautschi I. Horisberger J.D. Rossier B.C. Nature. 1994; 367: 463-467Crossref PubMed Scopus (1739) Google Scholar, 6Firsov D. Schild L. Gautschi I. Merillat A.M. Schneeberger E. Rossier B.C. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 15370-15375Crossref PubMed Scopus (388) Google Scholar). In vivo, the constitutive inactivation of the α-subunit of ENaC leads to complete abolishment of ENaC activity, and αENaC knockout animals die within 40 h after birth due to lung clearance failure (7Hummler E. Rossier B.C. Kid. Blood Press. Res. 1996; 19: 160-165Crossref PubMed Scopus (17) Google Scholar). Further gene targeting experiments clearly demonstrated that β- and γENaC (Scnn1b and Scnn1g) subunits are important for survival with the channel composed of the remaining subunits (αβ or αγ) conferring less channel activity (4Canessa C.M. Schild L. Buell G. Thorens B. Gautschi I. Horisberger J.D. Rossier B.C. Nature. 1994; 367: 463-467Crossref PubMed Scopus (1739) Google Scholar, 6Firsov D. Schild L. Gautschi I. Merillat A.M. Schneeberger E. Rossier B.C. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 15370-15375Crossref PubMed Scopus (388) Google Scholar, 8Pradervand S. Barker P. Wang Q. Ernst S.A. Beermann F. Grubb B. Burnier M. Schmidt A. Bindels R.J.M. Gatzy J. Rossier B.C. Hummler E. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 1732-1737Crossref PubMed Scopus (114) Google Scholar). This may also explain the distinct clinical phenotypes observed (9Barker P.M. Ngugen M.S. Gatzy J.T. Grubb B. Norman H. Hummler E. Rossier B. Boucher R.C. Koller B. J. Clin. Invest. 1998; 102: 1634-1640Crossref PubMed Scopus (223) Google Scholar, 10McDonald F.J. Yang B. Hrstka R.F. Drummond H.A. Tarr D.E. McCray Jr., P.B. Stokes J.B. Welsh M.J. Williamson R.A. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 1727-1731Crossref PubMed Scopus (216) Google Scholar). In human, mutations in all three ENaC subunits are reported to result in either ENaC hyper- or hypo-function associated with hypertension (Liddle syndrome) or salt-wasting syndrome (pseudohypoaldosteronism type-1, see for review Ref. 1Hummler E. Vallon V. J. Am. Soc. Nephrol. 2005; 16: 3160-3166Crossref PubMed Scopus (29) Google Scholar). epithelial sodium channel phosphate-buffered saline transepidermal water loss 4′,6-diamidino-2-phenylindole stratum granulosum stratum spinosum stratum corneum ceramide. epithelial sodium channel phosphate-buffered saline transepidermal water loss 4′,6-diamidino-2-phenylindole stratum granulosum stratum spinosum stratum corneum ceramide. ENaC expression has been demonstrated in skin of amphibians and in hair follicles, interfollicular epidermis, and sweat glands of mammals (11Puoti A. May A. Canessa C.M. Horisberger J-D. Schild L. Rossier B.C. Am. J. Physiol. 1995; 269: C188-C197Crossref PubMed Google Scholar, 12Oda Y. Imanzahrai A. Kwong A. Komuves L. Elias P.M. Largman C. Mauro T. J. Invest. Dermatol. 1999; 113: 796-801Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar, 13Brouard M. Casado M. Djelidi S. Barrandon Y. Farman N. J. Cell Sci. 1999; 112: 3343-3352PubMed Google Scholar). All three subunits (Scnn1a, Scnn1b, and Scnn1g) are found in mouse and human keratinocytes (12Oda Y. Imanzahrai A. Kwong A. Komuves L. Elias P.M. Largman C. Mauro T. J. Invest. Dermatol. 1999; 113: 796-801Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar, 13Brouard M. Casado M. Djelidi S. Barrandon Y. Farman N. J. Cell Sci. 1999; 112: 3343-3352PubMed Google Scholar). Interestingly, their expression level is increased in more differentiated keratinocytes and only found in the later stages of fetal epidermal development. In human epidermis, ENaC mRNA is expressed throughout adulthood, but is absent in 10-week-old fetal epidermis (12Oda Y. Imanzahrai A. Kwong A. Komuves L. Elias P.M. Largman C. Mauro T. J. Invest. Dermatol. 1999; 113: 796-801Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar, 13Brouard M. Casado M. Djelidi S. Barrandon Y. Farman N. J. Cell Sci. 1999; 112: 3343-3352PubMed Google Scholar). Patch clamp recordings of human keratinocytes reveal a sodium channel conductance that is blocked by benzamil with similar affinity and voltage dependence of the amiloride block as previously described for ENaC (13Brouard M. Casado M. Djelidi S. Barrandon Y. Farman N. J. Cell Sci. 1999; 112: 3343-3352PubMed Google Scholar). Further evidence that ENaC-mediated Na+ transport may be implicated in keratinocyte and epidermal differentiation comes from the previous analysis of newborn αENaC knockout mice, which exhibit epidermal thickening and premature lipid secretion in the upper epidermis, suggesting that ENaC-mediated sodium ion fluxes control selective aspects of keratinocyte differentiation (14Mauro T. Guitard M. Behne M. Oda Y. Crumrine D. Komuves L. Rassner U. Elias P.M. Hummler E. J. Invest. Dermatol. 2002; 118: 589-594Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar). The skin is a physical barrier at the interface between an organism and its environment preventing water loss and withstanding mechanical, chemical, and microbial assaults. To perform these functions, the epidermis as outer layer of the skin undergoes keratinization, a process in which epidermal cells progressively mature from basal cells with proliferative to of the stratum This differentiation is accompanied by in gene and of that control and lipid D. 1995; PubMed Scopus Google Scholar). in of these or has therefore the to the barrier function of the skin and to the important by ENaC in the whole body sodium ion to reveal its physiological in birth, in physiological be but a hours αENaC knockout mice a severe transepidermal water loss, and impairment of the barrier function due to highly lipid secretion and This dehydration is accompanied by of the skin surface Our data demonstrate that sodium channel is not required for of the epidermal barrier function but for barrier function in postnatal αENaC and by mice for the αENaC E. Barker P. Gatzy J. Beermann F. C. Schmidt A. Boucher Rossier B.C. 1996; PubMed Scopus Google and after birth. by as described E. Barker P. C. Wang Q. C. Grubb B. Gatzy J. Burnier M. Horisberger J-D. Beermann F. Boucher Rossier B.C. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). All experiments a and maintenance and by birth, knockout animals a as found by Hummler and E. Barker P. C. Wang Q. C. Grubb B. Gatzy J. Burnier M. Horisberger J-D. Beermann F. Boucher Rossier B.C. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google but for skin only animals syndrome been for mice and to dehydration and as described previously E. D. J. Y. Y. M. D. T. M. J. Cell PubMed Scopus Google Scholar). in at in in and with a C. I. Guitard M. S. B. Hummler E. J. Cell 2005; PubMed Scopus Google Scholar). of the of transepidermal water loss from the skin of newborn mice by a and as described previously M. F. A. C. S. E. Y. H. M. H. M. M. G. T. J. Proc. Natl. Acad. Sci. U. S. A. 1998; PubMed Scopus Google Scholar). the of loss C. I. Guitard M. S. B. Hummler E. J. 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All data are expressed as of to the of mice in by the for To the of the and level of as significant for all of the in the physiological of ENaC deficiency in the skin, the of the epidermis by a across the epidermal at birth, from the knockout not increased with the and the mice the barrier function by a dehydration the in body weight as a function of The dehydration of body in the knockout h after birth, the dehydration at h after birth water loss in the control and, at 6 h after birth, the in dehydration of their body weight with in the control and the skin by Although the not within the h the three knockout between and h after birth do a increased in from the at an early h) and late h) after birth, clearly a in the in the and with whereas the knockout to the basal This that the skin of the knockout mice may not to the environment data that αENaC expression is required to the epidermal barrier αENaC for of the an for in epidermal the distribution as well as the expression of differentiation revealed that a for the stratum expressed in epidermal basal cells of and knockout the distribution of an and the epidermal differentiation and similar in skin from and knockout mice observed in the stratum granulosum and in the stratum corneum in the but also found in the and in the stratum spinosum In the expression of 6 that to the outer of the hair in mice, expressed throughout the interfollicular epidermis in knockout animals for a The expression of the early and late differentiation by analysis of from to the and not In for of the and late differentiation in the knockout and skin barrier function may be by of tight junction in the analysis a distribution of tight junction in the whole epidermis for the and the layer of in the and a as for the of tight the barrier function of the tight of the and the the of the epidermis from stratum to the of the tight junction at the data clearly that the tight in the knockout This has been at and h after birth and the results at αENaC in and and of differentiation seem not to be the tight analysis lipid the lipid lipids, lamellar lipids, and covalently bound at h after birth, and with the lipid at h after birth In the mice, and cholesterol weight whereas the level of the The are of lipids, S. M. H. F. A. Y. J. Invest. Dermatol. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, T. A. G. Elias P.M. J. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, T. 1999; PubMed Scopus Google Y. M. H. E. S. F. A. Elias P.M. S. J. Res. Full Text Full Text PDF PubMed Google and cholesterol E. J. M. A. Elias P.M. J. Invest. Dermatol. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). The ceramide and are in the knockout mice In skin, the level of cholesterol is increased to h) and of mice at h after birth. Interestingly, the mice an between the and knockout dehydration and body weight loss are not from the control and Further of the and that the observed in all the and to be with h with the covalently bound lipids are important for the lamellar lipid and, the barrier function, the lipids of the and lipids by The of and decreased in the knockout and observed at and whereas the lipid these data a lipid composition with formation of the lamellar lipids of the lipid in the αENaC knockout in a lipid in a Ultrastructural analysis of knockout mouse skin h after morphological changes in the formation of intercellular lamellar lipids at the interface between the layer and body secretion and formation of the lamellar lipids proved abnormal and with and The of the keratinocyte layer highly lamellar lipids in the lipids to be in lamellar lipid the between the stratum corneum This results in the formation of abnormal lamellar at the interface between the and The lamellar in the of the stratum corneum In in animals and the lipid and to the well lipid pH in αENaC skin in and αENaC mice, found a of skin surface pH within the of from to not The skin surface pH as found in Interestingly, h after birth, a at which all three and within the the a significant in a skin surface pH of in the knockout with in the control a failure to complete ENaC in the of the as the is to the environment and as a and of body The epidermal barrier function of the skin the of water and and the physical barrier at the interface between and In gene inactivation of the α-subunit of the highly amiloride-sensitive epithelial sodium channel leads to distinct epidermal and which in a barrier within the birth, αENaC are not from their and and the barrier not and Ref. 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In conclusion, results the physiological of the epithelial sodium channel deficiency in skin that leads to distinct phenotypes in postnatal that ENaC an important in the of the postnatal epidermal barrier the physiological of αENaC deficiency in mouse skin to a of the to epidermal barrier function in the for the and mouse the of for analysis and the from the of for with the also for and and for the and Rossier for the also of the Hummler for and with