Hyperosmolar Mannitol Stimulates Expression of Aquaporins 4 and 9 through a p38 Mitogen-activated Protein Kinase-dependent Pathway in Rat Astrocytes

Abstract

The membrane pore proteins, aquaporins (AQPs), facilitate the osmotically driven passage of water and, in some instances, small solutes. Under hyperosmotic conditions, the expression of some AQPs changes, and some studies have shown that the expression of AQP1 and AQP5 is regulated by MAPKs. However, the mechanisms regulating the expression of AQP4 and AQP9 induced by hyperosmotic stress are poorly understood. In this study, we observed that hyperosmotic stress induced by mannitol increased the expression of AQP4 and AQP9 in cultured rat astrocytes, and intraperitoneal infusion of mannitol increased AQP4 and AQP9 in the rat brain cortex. In addition, a p38 MAPK inhibitor, but not ERK and JNK inhibitors, suppressed their expression in cultured astrocytes. AQPs play important roles in maintaining brain homeostasis. The expression of AQP4 and AQP9 in astrocytes changes after brain ischemia or traumatic injury, and some studies have shown that p38 MAPK in astrocytes is activated under similar conditions. Since mannitol is commonly used to reduce brain edema, understanding the regulation of AQPs and p38 MAPK in astrocytes under hyperosmotic conditions induced with mannitol may lead to a control of water movements and a new treatment for brain edema. The membrane pore proteins, aquaporins (AQPs), facilitate the osmotically driven passage of water and, in some instances, small solutes. Under hyperosmotic conditions, the expression of some AQPs changes, and some studies have shown that the expression of AQP1 and AQP5 is regulated by MAPKs. However, the mechanisms regulating the expression of AQP4 and AQP9 induced by hyperosmotic stress are poorly understood. In this study, we observed that hyperosmotic stress induced by mannitol increased the expression of AQP4 and AQP9 in cultured rat astrocytes, and intraperitoneal infusion of mannitol increased AQP4 and AQP9 in the rat brain cortex. In addition, a p38 MAPK inhibitor, but not ERK and JNK inhibitors, suppressed their expression in cultured astrocytes. AQPs play important roles in maintaining brain homeostasis. The expression of AQP4 and AQP9 in astrocytes changes after brain ischemia or traumatic injury, and some studies have shown that p38 MAPK in astrocytes is activated under similar conditions. Since mannitol is commonly used to reduce brain edema, understanding the regulation of AQPs and p38 MAPK in astrocytes under hyperosmotic conditions induced with mannitol may lead to a control of water movements and a new treatment for brain edema. Water passes across cell membranes substantially faster than can be explained by simple diffusion. This is necessary for the active regulation of water homeostasis under conditions of osmotic stress in the kidneys, lungs, brain, etc., and to meet these needs, a family of membrane channel proteins evolved. These proteins, termed “aquaporins” (AQPs), 1The abbreviations used are: AQP, aquaporin; MAPK, mitogen-activated protein kinase; ERK, extracellular signal-regulated kinase; JNK, c-Jun NH2-terminal kinase; GFAP, glial fibrillary acidic protein; l-DMEM, low glucose Dulbecco's modified Eagle's medium; RT, reverse transcriptase; TK, thymidine kinase; MEK, mitogen-activated protein kinase/extracellular signal-regulated kinase kinase. are found in all life forms, including archaea, eubacteria, fungi, plants, and all animal phyla (1Ishibashi K. Kuwahara M. Sasaki S. Rev. Physiol. Biochem. Pharmacol. 2000; 141: 1-32Crossref PubMed Google Scholar, 2Agre P. Bonhivers M. Borgnia M.J. J. Biol. 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Yoneda K. Asai K. Sobue K. Tada T. Fujita Y. Katsuya H. Fujita M. Aihara N. Mase M. Yamada K. Miura Y. Kato T. Brain Res. Mol. Brain Res. 2001; 90: 26-38Crossref PubMed Scopus (145) Google Scholar). found that the expression of AQP4 and AQP9 is induced in cultured rat astrocytes and in rat brain by hyperosmotic In addition, we that this and of the p38 MAPK in cultured rat astrocytes. this the of osmotic regulation of AQP4 and AQP9 and the evidence that the expression of AQP4 and AQP9 is regulated by the p38 MAPK Cell of astrocytes rat to T. Biochim. Biophys. Acta. PubMed Scopus Google Scholar). and cells cultured in low glucose Dulbecco's modified Eagle's with for the cells and in The cell of astrocytes as by with fibrillary acidic protein In AQP4 and AQP9 are in astrocytes but not in and (10Yamamoto N. Yoneda K. Asai K. Sobue K. Tada T. Fujita Y. Katsuya H. Fujita M. Aihara N. Mase M. Yamada K. Miura Y. Kato T. Brain Res. Mol. 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The AQP4 is regulated by of and The of the to to the of and the to to the of the and to to in the and to in the to the the The of AQP9 to to the by a similar the a with and to the The of for by of for for and for and in a of with of a to The with the same of the and a to The and the The to to to in the AQP9 to the Cell and AQP4 and AQP9 of the in the with the kinase the under control of the as astrocytes in with in a for and in with of the and of of of after of or mannitol in the astrocytes and The of control and in of in animal studies after the by the and of of used with and under a infusion a of a Am. J. Physiol. Google Scholar). the by and to of the The to under a of 5 of of of of of of or a hyperosmotic mannitol of mannitol to the by intraperitoneal infusion infusion The infusion and the of the infusion 1, 3, or and but not the of the the the infusion and for as the of the brain and for and osmotic pressure by the as the brain in by the Y. K. S. M. Y. Am. J. Google Scholar). in for in and and in and with the the with they with in for to in a of for to and after to they for with or in with The with for with the and with a for the with the by them in and The with are as of four by of with for all and the by for with of AQP4 and AQP9 in to the of hyperosmotic stress the expression of AQP4 and AQP9 and proteins, astrocytes in control osmotic pressure or hyperosmotic with or mannitol for of for or for AQP4 and AQP9 and proteins 1, and increased after treatment with 1, 3, and AQP4 and AQP9 and AQP4 protein increased after treatment with AQP9 protein after treatment with AQP4 and AQP9 and proteins induced to a with the of the of AQP4 and AQP9 astrocytes with hyperosmotic mannitol for various of AQP4 increased after 1, 3, and of treatment with and AQP9 increased after 3, and of treatment AQP to AQP4 and AQP9 proteins increased after of treatment with mannitol 2, and AQP4 to the after of treatment with AQP4 protein the same that this is regulated the and AQP9 protein but to the after of treatment with hyperosmotic of AQP4 and AQP9 protein astrocytes in hyperosmotic mannitol with or the protein inhibitor, for The increased expression of AQP induced by mannitol not affected by that protein is not hyperosmotic of AQP4 and AQP9 is astrocytes in or hyperosmotic with or mannitol for and the expression of AQP4 and AQP9 and proteins, they by and increased by mannitol and for the of hyperosmotic of AQP4 and AQP9 similar to those for and Y. 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PubMed Scopus Google Scholar, S. H. T. Y. E. J. Biol. Chem. 270: Full Text Full Text PDF PubMed Scopus Google Scholar, Z. Science. PubMed Scopus Google Scholar). Under hyperosmotic conditions, AQP1 is regulated by all F. Schrier R.W. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), and AQP5 is regulated by ERK J.D. Leitch V. Agre P. King L.S. J. Biol. Chem. 2000; 275: 9070-9077Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar). In study, all as by a In addition, the of of p38 MAPK, ERK, and JNK for their AQP4 and AQP9 by hyperosmotic the p38 MAPK suppressed AQP4 and AQP9 that AQP4 and AQP9 expression in rat astrocytes under hyperosmotic conditions can be regulated by the p38 MAPK the but not increased AQP4 and AQP9 are of p38 MAPK, stress that by than the kinase protein kinase and J. 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Full Text Full Text PDF PubMed Scopus Google Scholar). the found in the of AQP4 and of the increased under hyperosmotic conditions, not The that a for is and the a of the AQP9 for the is to be and but are present in this The of the AQP1 is not present in the AQP4 and AQP9 that under hyperosmotic conditions AQP4 and AQP9 are regulated by as In addition, the for p38 MAPK not been is to the that the expression of AQP4 and AQP9 under hyperosmotic conditions. to the regulating the expression of AQP4 and AQP9 in rat astrocytes, been that protein kinase and protein kinase play important of the cells with a protein kinase increased the expression of AQP9 in a and but the expression of AQP4 not N. Sobue K. Fujita M. Katsuya H. Asai K. Brain Res. Mol. Brain Res. 2002; PubMed Scopus (43) Google Scholar). treatment of the cells with a protein kinase in the expression of AQP4 and AQP9 in a and treatment N. Sobue K. T. M. Miura Y. Katsuya H. Asai K. Brain Res. Mol. 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Yamamoto for