Long-term dexamethasone treatment diminishes store-operated Ca~(2+) entry in salivary acinar cells
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摘要
Corticosteroids are used in the treatment of many diseases; however, they also induce various side effects. Dexamethasone is one of the most potent corticosteroids, and it has been reported to induce the side effect of impaired salivary gland function. This study aimed to evaluate the effects of dexamethasone on mouse submandibular gland function to gain insight into the mechanism of dexamethasone-induced salivary hypofunction. The muscarinic agonist carbachol(CCh) induced salivary secretion and was not affected by short-term dexamethasone treatment but was decreased following long-term dexamethasone administration. The expression levels of the membrane proteins Na~+-K~+-2 Cl-cotransporter, transmembrane member 16 A, and aquaporin 5 were comparable between the control and long-term dexamethasone treatment groups. The CCh-induced increase in calcium concentration was significantly lower in the presence of extracellular Ca~(2+) in the long-term dexamethasone treatment group compared to that in the control group. Furthermore, CCh-induced salivation in the absence of extracellular Ca~(2+) and Ca~(2+) ionophore A23187-induced salivation was comparable between the control and long-term dexamethasone treatment groups.Moreover, salivation induced by the Ca~(2+) -ATPase inhibitor thapsigargin was diminished in the long-term dexamethasone treatment group. In summary, these results demonstrate that short-term dexamethasone treatment did not impair salivary gland function, whereas long-term dexamethasone treatment diminished store-operated Ca~(2+) entry, resulting in hyposalivation in mouse submandibular glands.
Corticosteroids are used in the treatment of many diseases; however, they also induce various side effects. Dexamethasone is one of the most potent corticosteroids, and it has been reported to induce the side effect of impaired salivary gland function. This study aimed to evaluate the effects of dexamethasone on mouse submandibular gland function to gain insight into the mechanism of dexamethasone-induced salivary hypofunction. The muscarinic agonist carbachol(CCh) induced salivary secretion and was not affected by short-term dexamethasone treatment but was decreased following long-term dexamethasone administration. The expression levels of the membrane proteins Na~+-K~+-2 Cl-cotransporter, transmembrane member 16 A, and aquaporin 5 were comparable between the control and long-term dexamethasone treatment groups. The CCh-induced increase in calcium concentration was significantly lower in the presence of extracellular Ca~(2+) in the long-term dexamethasone treatment group compared to that in the control group. Furthermore, CCh-induced salivation in the absence of extracellular Ca~(2+) and Ca~(2+) ionophore A23187-induced salivation was comparable between the control and long-term dexamethasone treatment groups.Moreover, salivation induced by the Ca~(2+) -ATPase inhibitor thapsigargin was diminished in the long-term dexamethasone treatment group. In summary, these results demonstrate that short-term dexamethasone treatment did not impair salivary gland function, whereas long-term dexamethasone treatment diminished store-operated Ca~(2+) entry, resulting in hyposalivation in mouse submandibular glands.
Corticosteroids are used in the treatment of many diseases; however, they also induce various side effects. Dexamethasone is one of the most potent corticosteroids, and it has been reported to induce the side effect of impaired salivary gland function. This study aimed to evaluate the effects of dexamethasone on mouse submandibular gland function to gain insight into the mechanism of dexamethasone-induced salivary hypofunction. The muscarinic agonist carbachol(CCh) induced salivary secretion and was not affected by short-term dexamethasone treatment but was decreased following long-term dexamethasone administration. The expression levels of the membrane proteins Na~+-K~+-2 Cl-cotransporter, transmembrane member 16 A, and aquaporin 5 were comparable between the control and long-term dexamethasone treatment groups. The CCh-induced increase in calcium concentration was significantly lower in the presence of extracellular Ca~(2+) in the long-term dexamethasone treatment group compared to that in the control group. Furthermore, CCh-induced salivation in the absence of extracellular Ca~(2+) and Ca~(2+) ionophore A23187-induced salivation was comparable between the control and long-term dexamethasone treatment groups.Moreover, salivation induced by the Ca~(2+) -ATPase inhibitor thapsigargin was diminished in the long-term dexamethasone treatment group. In summary, these results demonstrate that short-term dexamethasone treatment did not impair salivary gland function, whereas long-term dexamethasone treatment diminished store-operated Ca~(2+) entry, resulting in hyposalivation in mouse submandibular glands.
引文
1.Trence,D.L.Management of patients on chronic glucocorticoid therapy:an endocrine perspective.Prim.Care 30,593-605(2003).
2.Dixon,W.G.,Suissa,S.&Hudson,M.The association between systemic glucocorticoid therapy and the risk of infection in patients with rheumatoid arthritis:systematic review and meta-analyses.Arthritis Res.Ther.13,R139(2011).
3.Costello,R.,Patel,R.,Humphreys,J.,McBeth,J.&Dixon,W.G.Patient perceptions of glucocorticoid side effects:a cross-sectional survey of users in an online health community.BMJ Open 7,e014603(2017).
4.Bordag,N.et al.Glucocorticoid(dexamethasone)-induced metabolome changes in healthy males suggest prediction of response and side effects.Sci.Rep.5,15954(2015).
5.Rooman,R.,Koster,G.,Bloemen,R.,Gresnigt,R.&van Buul-Offers,S.C.The effect of dexamethasone on body and organ growth of normal and IGF-II-transgenic mice.J.Endocrinol.163,543-552(1999).
6.Sreebny,L.M.&Schwartz,S.S.A reference guide to drugs and dry mouth.Gerodontology 14,33-47(1997).
7.Smidt,D.,Torpet,L.A.,Nauntofte,B.,Heegaard,K.M.&Pedersen,A.M.Associations between oral and ocular dryness,labial and whole salivary flow rates,systemic diseases and medications in a sample of older people.Commun.Dent.Oral.Epidemiol.39,276-288(2011).
8.Johnson,D.A.,Etzel,K.R.,Alvares,O.F.&Cortez,J.E.Regulation of parotid salivary proteins by glucocorticoids.J.Dent.Res.66,1563-1568(1987).
9.Bighetti,B.B.et al.Long-term dexamethasone treatment alters the histomorphology of acinar cells in rat parotid and submandibular glands.Int.J.Exp.Pathol.95,351-363(2014).
10.Edgar,W.M.Saliva:its secretion,composition and functions.Br.Dent.J.172,305-312(1992).
11.Humphrey,S.P.&Williamson,R.T.A review of saliva:normal composition,flow,and function.J.Prosthet.Dent.85,162-169(2001).
12.Nauntofte,B.Regulation of electrolyte in salivary acinar cells.Am.J.Physiol.Gastrointest.Liver Physiol.26,823-837(1992).
13.Melvin,J.E.,Yule,D.,Shuttleworth,T.&Begenisich,T.Regulation of fluid and electrolyte secretion in salivary gland acinar cells.Annu.Rev.Physiol.67,445-469(2005).
14.Putney,J.W.Jr.Receptor-regulated calcium entry.Pharmacol.Ther.48,427-434(1990).
15.Ambudkar,I.S.Calcium signalling in salivary gland physiology and dysfunction.J.Physiol.594,2813-2824(2016).
16.Enger,T.B.,Aure,M.H.,Jensen,J.L.&Galtung,H.K.Calcium signaling and cell volume regulation are altered in Sj?gren’s syndrome.Acta Odontol.Scand.72,549-556(2014).
17.Romanenko,V.G.et al.Tmem16A encodes the Ca2+-activated Cl-channel in mouse submandibular salivary gland acinar cells.J.Biol.Chem.285,12990-13001(2010).
18.Catalán,M.A.et al.A fluid secretion pathway unmasked by acinar-specific Tmem16A gene ablation in the adult mouse salivary gland.Proc.Natl.Acad.Sci.USA 112,2263-2268(2015).
19.Ambudkar,I.S.Ca2+signaling and regulation of fluid secretion in salivary gland acinar cells.Cell Calcium 55,297-305(2014).
20.Evans,R.L.et al.Severe impairment of salivation in Na+/K+/2Cl-cotransporter(NKCC1)-deficient mice.J.Biol.Chem.275,26720-26726(2000).
21.Krane,C.M.et al.Salivary acinar cells from aquaporin 5-deficient mice have decreased membrane water permeability and altered cell volume regulation.J.Biol.Chem.276,23413-23420(2001).
22.Sugita,M.,Hirono,C.&Shiba,Y.Gramicidin-perforated patch recording revealed the oscillatory nature of secretory Cl-movements in salivary acinar cells.J.Gen.Physiol.124,59-69(2004).
23.Stoenoiu,M.S.et al.Corticosteroids induce expression of aquaporin-1 and increase transcellular water transport in rat peritoneum.J.Am.Soc.Nephrol.14,555-565(2003).
24.Laube,M.,Bossmann,M.&Thome,U.H.Glucocorticoids distinctively modulate the CFTR channel with possible implications in lung development and transition into extrauterine life.PLoS ONE 10,e0124833(2015).
25.Heise,N.et al.Effect of dexamethasone on Na+/Ca2+exchanger in dendritic cells.Am.J.Physiol.Cell Physiol.300,C1306-C1313(2011).
26.Koizumi,M.&Yada,T.Sub-chronic stimulation of glucocorticoid receptor impairs and mineralocorticoid receptor protects cytosolic Ca2+responses to glucose in pancreatic beta-cells.J.Endocrinol.197,221-229(2008).
27.Kadeba,P.I.et al.Regulation of store-operated calcium entry by FK506-binding immunophilins.Cell Calcium 53,275-285(2013).
28.Urbach,V.,Walsh,D.E.,Mainprice,B.,Bousquet,J.&Harvey,B.J.Rapid nongenomic inhibition of ATP-induced Cl-secretion by dexamethasone in human bronchial epithelium.J.Physiol.(Lond.)545,869-878(2002).
29.Verrière,V.A.et al.Rapid effects of dexamethasone on intracellular pH and Na+/H+exchanger activity in human bronchial epithelial cells.J.Biol.Chem.280,35807-35814(2005).
30.Prota,L.F.M.et al.Dexamethasone regulates CFTR expression in Calu-3 cells with the involvement of chaperones HSP70 and HSP90.PLoS ONE 7,e47405(2012).
31.Ghaisas,M.et al.Preventive effect of Sphaeranthus indicus during progression of glucocorticoid-induced insulin resistance in mice.Pharm.Biol.48,1371-1375(2010).
32.Sullivan,P.W.,Ghushchyan,V.H.,Globe,G.&Schatz,M.Oral corticosteroid exposure and adverse effects in asthmatic patients.J.Allergy Clin.Immunol.141,110-116.e7(2018).
33.Tamez-pérez,H.E.,Quintanilla-flores,D.L.,Rodríguez-gutiérrez,R.,GonzálezGonzález,J.G.&Tamez-Pe?a,A.L.Steroid hyperglycemia:prevalence,early detection and therapeutic recommendations:a narrative review.World J.Diabetes 6,1073-1081(2015).
34.Munemasa,T.et al.Salivary gland hypofunction in KK-Ay type 2 diabetic mice.J.Diabetes 10,18-27,https://doi.org/10.1111/1753-0407.12548(2018).
35.Sreebny,L.M.,Yu,A.,Green,A.&Valdini,A.Xerostomia in diabetes mellitus.Diabetes Care 15,900-904(1992).
36.Itagaki,K.et al.Dexamethasone stimulates store-operated calcium entry and protein degradation in cultured L6 myotubes through a phospholipase A(2)-dependent mechanism.Am.J.Physiol.Cell Physiol.298,C1127-C1139(2010).
37.Storer,C.L.,Dickey,C.A.,Galigniana,M.D.,Rein,T.&Cox,M.B.FKBP51 and FKBP52 in signaling and disease.Trends Endocrinol.Metab.22,481-490(2011).
38.Fagerberg,L.et al.Analysis of the human tissue-specific expression by genomewide integration of transcriptomics and antibody-based proteomics.Mol.Cell Proteom.13,397-406(2014).
39.Romanenko,V.G.,Nakamoto,T.,Srivastava,A.,Begenisich,T.&Melvin,J.E.Regulation of membrane potential and fluid secretion by Ca2+-activated K+channels in mouse submandibular glands.J.Physiol.581,801-817(2007).
40.Pe?a-Münzenmayer,G.et al.Ae4(Slc4a9)anion exchanger drives Cl-uptakedependent fluid secretion by mouse submandibular gland acinar cells.J.Biol.Chem.290,10677-10688(2015).
2.Dixon,W.G.,Suissa,S.&Hudson,M.The association between systemic glucocorticoid therapy and the risk of infection in patients with rheumatoid arthritis:systematic review and meta-analyses.Arthritis Res.Ther.13,R139(2011).
3.Costello,R.,Patel,R.,Humphreys,J.,McBeth,J.&Dixon,W.G.Patient perceptions of glucocorticoid side effects:a cross-sectional survey of users in an online health community.BMJ Open 7,e014603(2017).
4.Bordag,N.et al.Glucocorticoid(dexamethasone)-induced metabolome changes in healthy males suggest prediction of response and side effects.Sci.Rep.5,15954(2015).
5.Rooman,R.,Koster,G.,Bloemen,R.,Gresnigt,R.&van Buul-Offers,S.C.The effect of dexamethasone on body and organ growth of normal and IGF-II-transgenic mice.J.Endocrinol.163,543-552(1999).
6.Sreebny,L.M.&Schwartz,S.S.A reference guide to drugs and dry mouth.Gerodontology 14,33-47(1997).
7.Smidt,D.,Torpet,L.A.,Nauntofte,B.,Heegaard,K.M.&Pedersen,A.M.Associations between oral and ocular dryness,labial and whole salivary flow rates,systemic diseases and medications in a sample of older people.Commun.Dent.Oral.Epidemiol.39,276-288(2011).
8.Johnson,D.A.,Etzel,K.R.,Alvares,O.F.&Cortez,J.E.Regulation of parotid salivary proteins by glucocorticoids.J.Dent.Res.66,1563-1568(1987).
9.Bighetti,B.B.et al.Long-term dexamethasone treatment alters the histomorphology of acinar cells in rat parotid and submandibular glands.Int.J.Exp.Pathol.95,351-363(2014).
10.Edgar,W.M.Saliva:its secretion,composition and functions.Br.Dent.J.172,305-312(1992).
11.Humphrey,S.P.&Williamson,R.T.A review of saliva:normal composition,flow,and function.J.Prosthet.Dent.85,162-169(2001).
12.Nauntofte,B.Regulation of electrolyte in salivary acinar cells.Am.J.Physiol.Gastrointest.Liver Physiol.26,823-837(1992).
13.Melvin,J.E.,Yule,D.,Shuttleworth,T.&Begenisich,T.Regulation of fluid and electrolyte secretion in salivary gland acinar cells.Annu.Rev.Physiol.67,445-469(2005).
14.Putney,J.W.Jr.Receptor-regulated calcium entry.Pharmacol.Ther.48,427-434(1990).
15.Ambudkar,I.S.Calcium signalling in salivary gland physiology and dysfunction.J.Physiol.594,2813-2824(2016).
16.Enger,T.B.,Aure,M.H.,Jensen,J.L.&Galtung,H.K.Calcium signaling and cell volume regulation are altered in Sj?gren’s syndrome.Acta Odontol.Scand.72,549-556(2014).
17.Romanenko,V.G.et al.Tmem16A encodes the Ca2+-activated Cl-channel in mouse submandibular salivary gland acinar cells.J.Biol.Chem.285,12990-13001(2010).
18.Catalán,M.A.et al.A fluid secretion pathway unmasked by acinar-specific Tmem16A gene ablation in the adult mouse salivary gland.Proc.Natl.Acad.Sci.USA 112,2263-2268(2015).
19.Ambudkar,I.S.Ca2+signaling and regulation of fluid secretion in salivary gland acinar cells.Cell Calcium 55,297-305(2014).
20.Evans,R.L.et al.Severe impairment of salivation in Na+/K+/2Cl-cotransporter(NKCC1)-deficient mice.J.Biol.Chem.275,26720-26726(2000).
21.Krane,C.M.et al.Salivary acinar cells from aquaporin 5-deficient mice have decreased membrane water permeability and altered cell volume regulation.J.Biol.Chem.276,23413-23420(2001).
22.Sugita,M.,Hirono,C.&Shiba,Y.Gramicidin-perforated patch recording revealed the oscillatory nature of secretory Cl-movements in salivary acinar cells.J.Gen.Physiol.124,59-69(2004).
23.Stoenoiu,M.S.et al.Corticosteroids induce expression of aquaporin-1 and increase transcellular water transport in rat peritoneum.J.Am.Soc.Nephrol.14,555-565(2003).
24.Laube,M.,Bossmann,M.&Thome,U.H.Glucocorticoids distinctively modulate the CFTR channel with possible implications in lung development and transition into extrauterine life.PLoS ONE 10,e0124833(2015).
25.Heise,N.et al.Effect of dexamethasone on Na+/Ca2+exchanger in dendritic cells.Am.J.Physiol.Cell Physiol.300,C1306-C1313(2011).
26.Koizumi,M.&Yada,T.Sub-chronic stimulation of glucocorticoid receptor impairs and mineralocorticoid receptor protects cytosolic Ca2+responses to glucose in pancreatic beta-cells.J.Endocrinol.197,221-229(2008).
27.Kadeba,P.I.et al.Regulation of store-operated calcium entry by FK506-binding immunophilins.Cell Calcium 53,275-285(2013).
28.Urbach,V.,Walsh,D.E.,Mainprice,B.,Bousquet,J.&Harvey,B.J.Rapid nongenomic inhibition of ATP-induced Cl-secretion by dexamethasone in human bronchial epithelium.J.Physiol.(Lond.)545,869-878(2002).
29.Verrière,V.A.et al.Rapid effects of dexamethasone on intracellular pH and Na+/H+exchanger activity in human bronchial epithelial cells.J.Biol.Chem.280,35807-35814(2005).
30.Prota,L.F.M.et al.Dexamethasone regulates CFTR expression in Calu-3 cells with the involvement of chaperones HSP70 and HSP90.PLoS ONE 7,e47405(2012).
31.Ghaisas,M.et al.Preventive effect of Sphaeranthus indicus during progression of glucocorticoid-induced insulin resistance in mice.Pharm.Biol.48,1371-1375(2010).
32.Sullivan,P.W.,Ghushchyan,V.H.,Globe,G.&Schatz,M.Oral corticosteroid exposure and adverse effects in asthmatic patients.J.Allergy Clin.Immunol.141,110-116.e7(2018).
33.Tamez-pérez,H.E.,Quintanilla-flores,D.L.,Rodríguez-gutiérrez,R.,GonzálezGonzález,J.G.&Tamez-Pe?a,A.L.Steroid hyperglycemia:prevalence,early detection and therapeutic recommendations:a narrative review.World J.Diabetes 6,1073-1081(2015).
34.Munemasa,T.et al.Salivary gland hypofunction in KK-Ay type 2 diabetic mice.J.Diabetes 10,18-27,https://doi.org/10.1111/1753-0407.12548(2018).
35.Sreebny,L.M.,Yu,A.,Green,A.&Valdini,A.Xerostomia in diabetes mellitus.Diabetes Care 15,900-904(1992).
36.Itagaki,K.et al.Dexamethasone stimulates store-operated calcium entry and protein degradation in cultured L6 myotubes through a phospholipase A(2)-dependent mechanism.Am.J.Physiol.Cell Physiol.298,C1127-C1139(2010).
37.Storer,C.L.,Dickey,C.A.,Galigniana,M.D.,Rein,T.&Cox,M.B.FKBP51 and FKBP52 in signaling and disease.Trends Endocrinol.Metab.22,481-490(2011).
38.Fagerberg,L.et al.Analysis of the human tissue-specific expression by genomewide integration of transcriptomics and antibody-based proteomics.Mol.Cell Proteom.13,397-406(2014).
39.Romanenko,V.G.,Nakamoto,T.,Srivastava,A.,Begenisich,T.&Melvin,J.E.Regulation of membrane potential and fluid secretion by Ca2+-activated K+channels in mouse submandibular glands.J.Physiol.581,801-817(2007).
40.Pe?a-Münzenmayer,G.et al.Ae4(Slc4a9)anion exchanger drives Cl-uptakedependent fluid secretion by mouse submandibular gland acinar cells.J.Biol.Chem.290,10677-10688(2015).