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The expression of astrocytic NKCC1 increases in the acute phase of traumatic brain injury (TBI), which induces brain edema. Endothelin\u20101 (ET\u20101) is a factor that induces brain edema and regulates the expression of several pathology\u2010related genes in astrocytes. In the present study, we investigated the effect of ET\u20101 on NKCC1 expression in astrocytes. ET\u20101 (100\u2009nM)\u2010treated cultured astrocytes showed increased NKCC1 mRNA and protein levels. The effect of ET\u20101 on NKCC1 expression in cultured astrocytes was reduced by BQ788 (1\u2009\u03bcM), an ET\n                    <jats:sub>B<\/jats:sub>\n                    antagonist, but not by FR139317 (1\u2009\u03bcM), an ET\n                    <jats:sub>A<\/jats:sub>\n                    antagonist. The involvement of ET\u20101 in NKCC1 expression in TBI was examined using a fluid percussion injury (FPI) mouse model that replicates the pathology of TBI with high reproducibility. Administration of BQ788 (15\u2009nmol\/day) decreased FPI\u2010induced expressions of NKCC1 mRNA and protein, accompanied with a reduction of astrocytic activation. FPI\u2010induced brain edema was attenuated by BQ788 and NKCC1 inhibitors (azosemide and bumetanide). ET\u20101\u2010treated cultured astrocytes showed increased mRNA and protein expression of hypoxia\u2010inducible factor\u20101\u03b1 (HIF1\u03b1). Immunohistochemical observations of mouse cerebrum after FPI showed co\u2010localization of HIF1\u03b1 with GFAP\u2010positive astrocytes. Increased HIF1\u03b1 expression in the TBI model was reversed by BQ788. FM19G11 (an HIF inhibitor, 1\u2009\u03bcM) and HIF1\u03b1 siRNA suppressed ET\u2010induced increase in NKCC1 expression in cultured astrocytes. These results indicate that ET\u20101 increases NKCC1 expression in astrocytes through the activation of HIF1\u03b1.\n                  <\/jats:p>","DOI":"10.1002\/glia.24609","type":"journal-article","created":{"date-parts":[[2024,8,21]],"date-time":"2024-08-21T22:18:22Z","timestamp":1724278702000},"page":"2231-2246","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Endothelin\u20101 increases Na\n                    <sup>+<\/sup>\n                    \u2010K\n                    <sup>+<\/sup>\n                    \u2010\n                    <scp>2Cl<\/scp>\n                    <sup>\u2212<\/sup>\n                    cotransporter\u20101 expression in cultured astrocytes and in traumatic brain injury model: An involvement of\n                    <scp>HIF1\u03b1<\/scp>\n                    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