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Published in: Inflammation 5/2020

01-10-2020 | Pulmonary Edema | Original Article

Dexamethasone Upregulates the Expression of Aquaporin4 by Increasing SUMOylation in A549 Cells

Authors: Xiaoling Zhang, Xiaofang Ma, Yanxia Li, Weiheng Yan, Quan Zheng, Lili Li, Yulan Yan, Xiaozhi Liu, Jun Zheng

Published in: Inflammation | Issue 5/2020

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Abstract

Dexamethasone can alleviate the severity of bronchial and alveolar edema and therefore is widely applied in the treatment of various exudative diseases including pulmonary edema. However, the effectiveness of dexamethasone is still being questioned and its mechanism is not fully understood. Aquaporins (AQPs) are mainly responsible for the transmembrane transport of water, which is tightly associated with pulmonary edema. Small ubiquitin-like modifiers (SUMOs) are considered to play a protective role in some pathological conditions. In this study, we demonstrated that dexamethasone can upregulate the expression of AQPs in A549 cells by inducing SUMOylation. We found that a low dose of dexamethasone significantly upregulated the levels of SUMOylation and AQP expression in A549 cells, accompanied by a translocation of SUMOs from the cytoplasm to the nucleus. We also explored the possible relation between SUMOylation and AQPs. Knockdown of SUMO2/3 by RNA interference decreased the level of AQP4 in A549 cells after dexamethasone stimulation. Together, our findings demonstrated that AQP4 expression was upregulated in A549 cells exposed to dexamethasone, and SUMOylation may participate in the regulation of AQP4.
Literature
1.
go back to reference Assaad, S., W.B. Kratzert, B. Shelley, M.B. Friedman, and A.J. Perrino. 2018. Assessment of pulmonary edema: Principles and practice. Journal of Cardiothoracic and Vascular Anesthesia 32: 901–914.CrossRef Assaad, S., W.B. Kratzert, B. Shelley, M.B. Friedman, and A.J. Perrino. 2018. Assessment of pulmonary edema: Principles and practice. Journal of Cardiothoracic and Vascular Anesthesia 32: 901–914.CrossRef
2.
go back to reference Herrero, R., G. Sanchez, and J.A. Lorente. 2018. New insights into the mechanisms of pulmonary edema in acute lung injury. Annals of Translational Medicine 6: 32.CrossRef Herrero, R., G. Sanchez, and J.A. Lorente. 2018. New insights into the mechanisms of pulmonary edema in acute lung injury. Annals of Translational Medicine 6: 32.CrossRef
3.
go back to reference Bartko, J., L. Stiebellehner, U. Derhaschnig, C. Schoergenhofer, M. Schwameis, H. Prosch, and B. Jilma. 2016. Dissociation between systemic and pulmonary anti-inflammatory effects of dexamethasone in humans. British Journal of Clinical Pharmacology 81: 865–877.CrossRef Bartko, J., L. Stiebellehner, U. Derhaschnig, C. Schoergenhofer, M. Schwameis, H. Prosch, and B. Jilma. 2016. Dissociation between systemic and pulmonary anti-inflammatory effects of dexamethasone in humans. British Journal of Clinical Pharmacology 81: 865–877.CrossRef
4.
go back to reference Takata, K., T. Matsuzaki, and Y. Tajika. 2004. Aquaporins: Water channel proteins of the cell membrane. Progress in Histochemistry and Cytochemistry 39: 1–83.CrossRef Takata, K., T. Matsuzaki, and Y. Tajika. 2004. Aquaporins: Water channel proteins of the cell membrane. Progress in Histochemistry and Cytochemistry 39: 1–83.CrossRef
5.
go back to reference Verkman, A.S., M.O. Anderson, and M.C. Papadopoulos. 2014. Aquaporins: Important but elusive drug targets. Nature Reviews. Drug Discovery 13: 259–277.CrossRef Verkman, A.S., M.O. Anderson, and M.C. Papadopoulos. 2014. Aquaporins: Important but elusive drug targets. Nature Reviews. Drug Discovery 13: 259–277.CrossRef
6.
go back to reference Li, J., M. Xu, Q. Fan, X. Xie, Y. Zhang, D. Mu, P. Zhao, B. Zhang, F. Cao, Y. Wang, F. Jin, and Z. Li. 2011. Tanshinone IIA ameliorates seawater exposure-induced lung injury by inhibiting aquaporins (AQP) 1 and AQP5 expression in lung. Respiratory Physiology & Neurobiology 176: 39–49.CrossRef Li, J., M. Xu, Q. Fan, X. Xie, Y. Zhang, D. Mu, P. Zhao, B. Zhang, F. Cao, Y. Wang, F. Jin, and Z. Li. 2011. Tanshinone IIA ameliorates seawater exposure-induced lung injury by inhibiting aquaporins (AQP) 1 and AQP5 expression in lung. Respiratory Physiology & Neurobiology 176: 39–49.CrossRef
7.
go back to reference Wu, Y., C.Y. Pan, C.Z. Guo, Z.J. Dong, Q. Wu, H.M. Dong, and W. Zhang. 2015. Expression of aquaporin 1 and 4 in rats with acute hypoxic lung injury and its significance. Genetics and Molecular Research 14: 12756–12764.CrossRef Wu, Y., C.Y. Pan, C.Z. Guo, Z.J. Dong, Q. Wu, H.M. Dong, and W. Zhang. 2015. Expression of aquaporin 1 and 4 in rats with acute hypoxic lung injury and its significance. Genetics and Molecular Research 14: 12756–12764.CrossRef
8.
go back to reference Day, R.E., P. Kitchen, D.S. Owen, C. Bland, L. Marshall, A.C. Conner, R.M. Bill, and M.T. Conner. 1840. Human aquaporins: Regulators of transcellular water flow. Biochimica et Biophysica Acta 2014: 1492–1506. Day, R.E., P. Kitchen, D.S. Owen, C. Bland, L. Marshall, A.C. Conner, R.M. Bill, and M.T. Conner. 1840. Human aquaporins: Regulators of transcellular water flow. Biochimica et Biophysica Acta 2014: 1492–1506.
9.
go back to reference Petrova, R.S., K.F. Webb, E. Vaghefi, K. Walker, K.L. Schey, and P.J. Donaldson. 2018. Dynamic functional contribution of the water channel AQP5 to the water permeability of peripheral lens fiber cells. American Journal of Physiology. Cell Physiology 314: C191–C201.CrossRef Petrova, R.S., K.F. Webb, E. Vaghefi, K. Walker, K.L. Schey, and P.J. Donaldson. 2018. Dynamic functional contribution of the water channel AQP5 to the water permeability of peripheral lens fiber cells. American Journal of Physiology. Cell Physiology 314: C191–C201.CrossRef
10.
go back to reference Galan-Cobo, A., E. Arellano-Orden, S.R. Sanchez, J.L. Lopez-Campos, R.C. Gutierrez, I.L. Gomez, N. Suarez-Luna, M. Molina-Molina, P.J. Rodriguez, and M. Echevarria. 2018. The expression of AQP1 IS modified in lung of patients with idiopathic pulmonary fibrosis: Addressing a possible new target. Frontiers in Molecular Biosciences 5: 43.CrossRef Galan-Cobo, A., E. Arellano-Orden, S.R. Sanchez, J.L. Lopez-Campos, R.C. Gutierrez, I.L. Gomez, N. Suarez-Luna, M. Molina-Molina, P.J. Rodriguez, and M. Echevarria. 2018. The expression of AQP1 IS modified in lung of patients with idiopathic pulmonary fibrosis: Addressing a possible new target. Frontiers in Molecular Biosciences 5: 43.CrossRef
11.
go back to reference Xiong, L.L., Y. Tan, H.Y. Ma, P. Dai, Y.X. Qin, R.A. Yang, Y.Y. Xu, Z. Deng, W. Zhao, Q.J. Xia, T.H. Wang, and Y.H. Zhang. 2016. Administration of SB239063, a potent p38 MAPK inhibitor, alleviates acute lung injury induced by intestinal ischemia reperfusion in rats associated with AQP4 downregulation. International Immunopharmacology 38: 54–60.CrossRef Xiong, L.L., Y. Tan, H.Y. Ma, P. Dai, Y.X. Qin, R.A. Yang, Y.Y. Xu, Z. Deng, W. Zhao, Q.J. Xia, T.H. Wang, and Y.H. Zhang. 2016. Administration of SB239063, a potent p38 MAPK inhibitor, alleviates acute lung injury induced by intestinal ischemia reperfusion in rats associated with AQP4 downregulation. International Immunopharmacology 38: 54–60.CrossRef
12.
go back to reference Flodby, P., C. Li, Y. Liu, H. Wang, M.E. Rieger, P. Minoo, E.D. Crandall, D.K. Ann, Z. Borok, and B. Zhou. 2017. Cell-specific expression of aquaporin-5 (Aqp5) in alveolar epithelium is directed by GATA6/Sp1 via histone acetylation. Scientific Reports 7: 3473.CrossRef Flodby, P., C. Li, Y. Liu, H. Wang, M.E. Rieger, P. Minoo, E.D. Crandall, D.K. Ann, Z. Borok, and B. Zhou. 2017. Cell-specific expression of aquaporin-5 (Aqp5) in alveolar epithelium is directed by GATA6/Sp1 via histone acetylation. Scientific Reports 7: 3473.CrossRef
13.
go back to reference Wimmer, P., S. Schreiner, and T. Dobner. 2012. Human pathogens and the host cell SUMOylation system. Journal of Virology 86: 642–654.CrossRef Wimmer, P., S. Schreiner, and T. Dobner. 2012. Human pathogens and the host cell SUMOylation system. Journal of Virology 86: 642–654.CrossRef
14.
go back to reference Hao, X., H. Wang, W. Liu, S. Liu, Z. Peng, Y. Sun, J. Zhao, Q. Jiang, and H. Liu. 2016. Enhanced expression levels of aquaporin-1 and aquaporin-4 in A549 cells exposed to silicon dioxide. Molecular Medicine Reports 14: 2101–2106.CrossRef Hao, X., H. Wang, W. Liu, S. Liu, Z. Peng, Y. Sun, J. Zhao, Q. Jiang, and H. Liu. 2016. Enhanced expression levels of aquaporin-1 and aquaporin-4 in A549 cells exposed to silicon dioxide. Molecular Medicine Reports 14: 2101–2106.CrossRef
15.
go back to reference Talamillo, A., D. Martin, R. Hjerpe, J. Sanchez, and R. Barrio. 2010. SUMO and ubiquitin modifications during steroid hormone synthesis and function. Biochemical Society Transactions 38: 54–59.CrossRef Talamillo, A., D. Martin, R. Hjerpe, J. Sanchez, and R. Barrio. 2010. SUMO and ubiquitin modifications during steroid hormone synthesis and function. Biochemical Society Transactions 38: 54–59.CrossRef
16.
go back to reference Lomeli, H., and M. Vazquez. 2011. Emerging roles of the SUMO pathway in development. Cellular and Molecular Life Sciences 68: 4045–4064.CrossRef Lomeli, H., and M. Vazquez. 2011. Emerging roles of the SUMO pathway in development. Cellular and Molecular Life Sciences 68: 4045–4064.CrossRef
17.
go back to reference Liu, X., W. Ren, Z. Jiang, Z. Su, X. Ma, Y. Li, R. Jiang, J. Zhang, and X. Yang. 2017. Hypothermia inhibits the proliferation of bone marrow-derived mesenchymal stem cells and increases tolerance to hypoxia by enhancing SUMOylation. International Journal of Molecular Medicine 40: 1631–1638.PubMedPubMedCentral Liu, X., W. Ren, Z. Jiang, Z. Su, X. Ma, Y. Li, R. Jiang, J. Zhang, and X. Yang. 2017. Hypothermia inhibits the proliferation of bone marrow-derived mesenchymal stem cells and increases tolerance to hypoxia by enhancing SUMOylation. International Journal of Molecular Medicine 40: 1631–1638.PubMedPubMedCentral
18.
go back to reference Enserink, J.M. 2015. Sumo and the cellular stress response. Cell Div 10: 4.CrossRef Enserink, J.M. 2015. Sumo and the cellular stress response. Cell Div 10: 4.CrossRef
19.
go back to reference Yang, W., and W. Paschen. 2015. SUMO proteomics to decipher the SUMO-modified proteome regulated by various diseases. Proteomics 15: 1181–1191.CrossRef Yang, W., and W. Paschen. 2015. SUMO proteomics to decipher the SUMO-modified proteome regulated by various diseases. Proteomics 15: 1181–1191.CrossRef
20.
go back to reference Marcelli, S., E. Ficulle, F. Iannuzzi, E. Kövari, R. Nisticò, and M. Feligioni. 2017. Targeting SUMO-1ylation contrasts synaptic dysfunction in a mouse model of Alzheimer’s disease. Molecular Neurobiology 54: 6609–6623.CrossRef Marcelli, S., E. Ficulle, F. Iannuzzi, E. Kövari, R. Nisticò, and M. Feligioni. 2017. Targeting SUMO-1ylation contrasts synaptic dysfunction in a mouse model of Alzheimer’s disease. Molecular Neurobiology 54: 6609–6623.CrossRef
21.
go back to reference Minnear, F.L., and R.S. Connell. 1982. Prevention of aconitine-induced neurogenic pulmonary edema (NPE) with hypovolemia or methylprednisolone. The Journal of Trauma 22: 121–128.CrossRef Minnear, F.L., and R.S. Connell. 1982. Prevention of aconitine-induced neurogenic pulmonary edema (NPE) with hypovolemia or methylprednisolone. The Journal of Trauma 22: 121–128.CrossRef
22.
go back to reference Faus, H., and B. Haendler. 2006. Post-translational modifications of steroid receptors. Biomedicine & Pharmacotherapy 60: 520–528.CrossRef Faus, H., and B. Haendler. 2006. Post-translational modifications of steroid receptors. Biomedicine & Pharmacotherapy 60: 520–528.CrossRef
23.
go back to reference Nie, M., and M.N. Boddy. 2016. Cooperativity of the SUMO and ubiquitin pathways in genome stability. Biomolecules 6: 14.CrossRef Nie, M., and M.N. Boddy. 2016. Cooperativity of the SUMO and ubiquitin pathways in genome stability. Biomolecules 6: 14.CrossRef
24.
go back to reference Pelisch, F., R. Sonneville, E. Pourkarimi, A. Agostinho, J.J. Blow, A. Gartner, and R.T. Hay. 2014. Dynamic SUMO modification regulates mitotic chromosome assembly and cell cycle progression in Caenorhabditis elegans. Nature Communications 5: 5485.CrossRef Pelisch, F., R. Sonneville, E. Pourkarimi, A. Agostinho, J.J. Blow, A. Gartner, and R.T. Hay. 2014. Dynamic SUMO modification regulates mitotic chromosome assembly and cell cycle progression in Caenorhabditis elegans. Nature Communications 5: 5485.CrossRef
25.
go back to reference Bossis, G., J.E. Sarry, C. Kifagi, M. Ristic, E. Saland, F. Vergez, T. Salem, H. Boutzen, H. Baik, F. Brockly, M. Pelegrin, T. Kaoma, L. Vallar, C. Récher, S. Manenti, and M. Piechaczyk. 2014. The ROS/SUMO axis contributes to the response of acute myeloid leukemia cells to chemotherapeutic drugs. Cell Reports 7: 1815–1823.CrossRef Bossis, G., J.E. Sarry, C. Kifagi, M. Ristic, E. Saland, F. Vergez, T. Salem, H. Boutzen, H. Baik, F. Brockly, M. Pelegrin, T. Kaoma, L. Vallar, C. Récher, S. Manenti, and M. Piechaczyk. 2014. The ROS/SUMO axis contributes to the response of acute myeloid leukemia cells to chemotherapeutic drugs. Cell Reports 7: 1815–1823.CrossRef
26.
go back to reference Li, G., X. Liu, Z. Su, and D. Zhang. 2017. Hypothermia exerts early neuroprotective effects involving protein conjugation of SUMO-2/3 in a rat model of middle cerebral artery occlusion. Molecular Medicine Reports 16: 3217–3223.CrossRef Li, G., X. Liu, Z. Su, and D. Zhang. 2017. Hypothermia exerts early neuroprotective effects involving protein conjugation of SUMO-2/3 in a rat model of middle cerebral artery occlusion. Molecular Medicine Reports 16: 3217–3223.CrossRef
27.
go back to reference Zhao, B., S.Q. Yao, and X.H. Hao. 2016. Expression of AQP-1 and AQP-4 in the lungs of drown rats. Fa Yi Xue Za Zhi 32: 321–325.PubMed Zhao, B., S.Q. Yao, and X.H. Hao. 2016. Expression of AQP-1 and AQP-4 in the lungs of drown rats. Fa Yi Xue Za Zhi 32: 321–325.PubMed
28.
go back to reference Zhang, J., L. Gong, B. Hasan, J. Wang, J. Luo, H. Ma, and F. Li. 2015. Use of aquaporins 1 and 5 levels as a diagnostic marker in mild-to-moderate adult-onset asthma. International Journal of Clinical and Experimental Pathology 8: 14206–14213.PubMedPubMedCentral Zhang, J., L. Gong, B. Hasan, J. Wang, J. Luo, H. Ma, and F. Li. 2015. Use of aquaporins 1 and 5 levels as a diagnostic marker in mild-to-moderate adult-onset asthma. International Journal of Clinical and Experimental Pathology 8: 14206–14213.PubMedPubMedCentral
Metadata
Title
Dexamethasone Upregulates the Expression of Aquaporin4 by Increasing SUMOylation in A549 Cells
Authors
Xiaoling Zhang
Xiaofang Ma
Yanxia Li
Weiheng Yan
Quan Zheng
Lili Li
Yulan Yan
Xiaozhi Liu
Jun Zheng
Publication date
01-10-2020
Publisher
Springer US
Published in
Inflammation / Issue 5/2020
Print ISSN: 0360-3997
Electronic ISSN: 1573-2576
DOI
https://doi.org/10.1007/s10753-020-01267-0

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