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Originally published In Press as doi:10.1074/jbc.M304368200 on August 27, 2003

J. Biol. Chem., Vol. 278, Issue 45, 44525-44534, November 7, 2003
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Hyperosmolar Mannitol Stimulates Expression of Aquaporins 4 and 9 through a p38 Mitogen-activated Protein Kinase-dependent Pathway in Rat Astrocytes*

Hajime Arima{ddagger}§, Naoki Yamamoto||, Kazuya Sobue§, Fuminori Umenishi**, Toyohiro Tada{ddagger}{ddagger}, Hirotada Katsuya§, and Kiyofumi Asai||

From the {ddagger}Department of Anesthesia and Critical Care, Okazaki City Hospital, 3-1 Goshoai, Koryuji-cho, Okazaki 444-8553, Japan, the §Department of Anesthesiology and Medical Crisis Management, Nagoya City University, Graduate School of Medical Sciences, Mizuho-ku, Nagoya 467-8601, Japan, the ||Department of Molecular Neurobiology, Nagoya City University, Graduate School of Medical Sciences, Mizuho-ku, Nagoya 467-8601, Japan, the **Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado 80262, and the {ddagger}{ddagger}Department of Pathology, Nagoya City University School of Nursing, Mizuho-ku, Nagoya 467-8601, Japan

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.


Received for publication, April 25, 2003 , and in revised form, August 14, 2003.

* This work was supported by a grant-in-aid for Scientific Research (C), a grant-in-aid for Exploratory Research, and a grant-in-aid for Young Scientists (A and B) from the Ministry of Education, Culture, Sports, Science and Technology of Japan and a Research Grant from the Japan Brain Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Anesthesia and Critical Care, Okazaki City Hospital, 3-1 Goshoai, Koryuji-cho, Okazaki 444-8553, Japan. Tel.: 81-564-21-8111; Fax: 81-564-25-2913; E-mail: arima{at}sb.starcat.ne.jp.


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